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Antimicrobial Aspects of Inflammatory Resolution in the Mucosa: A Role for Proresolving Mediators

This information is current as Eric L. Campbell, Charles N. Serhan and Sean P. Colgan of September 28, 2021. J Immunol 2011; 187:3475-3481; ; doi: 10.4049/jimmunol.1100150 http://www.jimmunol.org/content/187/7/3475 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Antimicrobial Aspects of Inflammatory Resolution in the Mucosa: A Role for Proresolving Mediators Eric L. Campbell,* Charles N. Serhan,† and Sean P. Colgan* Mucosal surfaces function as selectively permeable bar- what endogenous mechanisms control the magnitude and riers between the host and the outside world. Given duration of the acute response, particularly as they relate to their close proximity to microbial Ags, mucosal surfaces the cardinal signs of inflammation (2, 4). It has now become have evolved sophisticated mechanisms for maintaining evident that the resolution program of acute inflammation homeostasis and preventing excessive acute inflamma- particularly within mucosal surfaces remains to be uncovered, tory reactions. The role attributed to epithelial cells and that a complete understanding of these critical pathways was historically limited to serving as a selective barrier; will undoubtedly direct new therapeutic opportunities. in recent years, numerous findings implicate an active Inflammation at mucosal surfaces provides a unique setting Downloaded from role of the epithelium with proresolving mediators in for which to define resolution pathways. By their nature, mu- the maintenance of immunological equilibrium. In this cosal surfaces interact with the environment and thereby the brief review, we highlight new evidence that the epithe- microbial world in which we live. Important in this regard, the microbiota of each mucosal surface is unique. It is estimated, lium actively contributes to coordination and resolution for example, that the skin harbors 182 different bacterial of inflammation, principally through the generation of species, whereas the large intestine may support as many as http://www.jimmunol.org/ anti-inflammatory and proresolution lipid mediators. v v 1220 different bacterial phylotypes (5). Given this diversity These autacoids, derived from -6 and -3 polyunsat- of microbiota, it is not surprising that humans have evolved urated fatty acids, are implicated in the initiation, pro- unique mechanisms to counteract regular microbial chal- gression, and resolution of acute inflammation and lenges. Along these same lines, the timely resolution of on- display specific, epithelial-directed actions focused going local inflammation has evolved to these ever-changing on mucosal homeostasis. We also summarize present challenges. We are only now beginning to appreciate the unique knowledge of mechanisms for resolution via regulation features and importance of these responses.

of epithelial-derived antimicrobial in response In this brief review, we highlight recent discoveries that by guest on September 28, 2021 to proresolving lipid mediators. The Journal of impact the active resolution of mucosal inflammation. Given Immunology, 2011, 187: 3475–3481. their founding role in activeresolutionmechanisms,we have focused on the unique contributions of specialized proresolving mediators (SPMs), namely, the resolvins, lipid- he resolution of ongoing inflammation was histori- derived mediators that are agonist dependent, temporally cally considered a passive act of the healing process distinct, and functionally carry novel potent mucosa-directed T with dilution of proinflammatory chemical mediators signals (2). (1) and occurred independent of active biochemical pathways (1, 2). This view has changed in fundamental ways in the past Resolution-based pharmacology: a lesson from aspirin decade. It is now appreciated that uncontrolled inflammation Resolution of inflammation and return to tissue homeostasis is a unifying component in many diseases, and new evidence is an exceptionally well-coordinated process. SPMs generated indicates that inflammatory resolution is a biosynthetically during the resolution phase of ongoing inflammation acti- active process (3). These new findings implicate a tissue de- vely stimulate restoration of tissue homeostasis (3). The first cision process wherein acute inflammation, chronic inflam- resolvin, known today as resolvin E1 (RvE1), was identified in mation, or inflammatory resolution hold the answers as to 1999 as a potent and active initiator of resolution (4). In-

*Mucosal Inflammation Program, Department of Medicine, University of Colorado Address correspondence and reprint requests to Dr. Eric L. Campbell, Mucosal Inflam- School of Medicine, Aurora, CO 80045; and †Department of Anesthesiology, Perioper- mation Program, University of Colorado Denver, Mail Stop B-146, 12700 East 19th ative and Pain Medicine, Center for Experimental Therapeutics and , Avenue, Aurora, CO 80045. E-mail address: [email protected] Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 Abbreviations used in this article: AA, ; ALPI, intestinal alkaline phos- Received for publication May 20, 2011. Accepted for publication July 15, 2011. phatase; ASA, acetylsalicylic acid; ATL, aspirin-triggered ; BPI, bactericidal permeability-increasing protein; COX, ; DHA, docosahexaenoic acid; E.L.C. is supported by a fellowship from the Crohn’s and Colitis Foundation of Amer- EPA, eicosapentaenoic acid; LXA , lipoxin A (5S,6R,15S-trihydroxytrihydroxy-7E, ica. The S.P.C. laboratory is supported by National Institutes of Health Grants 4 4 9E,11Z,13E-eicosatetraenoic acid); PMN, polymorphonuclear leukocyte, ; R37DK50189 and RO1HL60569. The C.N.S. laboratory is supported by National PUFA, polyunsaturated fatty acid; RvD1, resolvin D1; RvE1, resolvin E1 (5S,6R,15S- Institutes of Health Grants R01GM038765 and R01DE019938. trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid); SPM, specialized proresolving mediator. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 and Kidney Diseases; the National Institute of General Medical Sciences; the National Heart, Lung, and Blood Institute; the National Institute of Dental and Craniofacial Research; or the National Institutes of Health. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1100150 3476 BRIEF REVIEWS: ANTIMICROBIALS AND INFLAMMATORY RESOLUTION ordinate, unrestricted, acute inflammation is now acknowl- edged as an instigating factor, which, when unchecked, con- tributes to numerous chronic disease states, including cardio- vascular disease, metabolic disorders, and . As such, an understanding of the pharmacology of anti-inflammation and endogenous proresolution has been a significant ven- ture (2). As a basic feature, cyclooxygenase-2 (COX-2) contributes fundamentally to both inflammation and resolution (6, 7). COX-2 expression is rapidly induced at sites of inflammation and is a key enzyme in the generation of PGs, via its oxy- genase and peroxidase activities (7). In brief, after liberation of the v-6 fatty acid arachidonic acid (AA) from mem- branes via phospholipase A2, the oxygenase function of COX-2 catalyzes AA to PGG2 and subsequently to PGH2 via the peroxidase activity of the enzyme. Nonsteroidal anti- inflammatory drugs lower the amplitude of inflammation and delay resolution (6, 8). Acetylsalicylic acid (ASA, aspirin), Downloaded from stands apart in that it inhibits proinflammatory signals and accelerates resolution (9). ASA irreversibly acetylates COX-2 on 516, rendering it incapable of converting AA to PGG2. In its acetylated state, ASA produces 15R-H(P)ETE and its peroxidase activity remains intact, resulting in for- mation of 15R-hydroxyeicosatetraenoate. Aside from ASA’s http://www.jimmunol.org/ anti-inflammatory action of inhibiting PG synthesis, 15R- hydroxyeicosatetraenoate is a precursor for proresolution 15- epi- (10). Such aspirin-triggered lipoxins (ATLs) are FIGURE 1. “Class switching” in the lipid metabolome promotes reso- more resistant to metabolic inactivation than lipoxins (11) lution. Enzymes COX-1 and COX-2 convert AA to PGG2 by cyclo- oxygenation, and subsequently to PGH2 by peroxidation. In turn, PGH2 is and also assert anti-inflammatory and proresolving activities metabolized to PGs and thromboxanes via specific synthases (top panel). ASA- in a wide range of inflammatory diseases (7, 8). In addition to mediated acetylation of COX enzymes inhibits the cyclooxygenation in the arachidonate-derived lipoxins and ATLs, bioactive SPMs COX-1, but COX-2 retains activity (see Refs. 4 and 87 for further details). v Proresolving SPMs are produced via acetylated COX-2 with substrates are also biosynthesized from the -3 polyunsaturated fatty by guest on September 28, 2021 acids (PUFAs). Both eicosapentaenoic acid (EPA) and doco- AA and the v substrates EPA and DHA (bottom panel). Lipoxygenases in sahexaenoic acid (DHA) are precursors in the biosynthesis of human, mouse, and fish tissues can also initiate the biosynthesis of 17S- containing resolvins and protectins de novo. both aspirin-triggered forms of the E- and D-series resolvins. Of importance, lipoxygenases can initiate the biosynthesis of resolvins (both E- and D-series), as well as protectins and flammation of the periodontium (21) and stimulates the maresins, without ASA treatment (3) (see Fig. 1). These are clearance of apoptotic cell from mucosal surfaces (22). The the main pathways for SPM biosynthesis in the absence of protective role of RvE1 in has been at- ASA treatment. Other nonsteroidal anti-inflammatory drugs tributed to both diminished inflammation and curtailed (i.e., indomethacin) can both block the biosynthesis of the -dependent destruction of bone (23). In the gastro- aspirin-triggered forms of SPM and lead to enhanced for- intestinal tract, RvE1 is protective in murine models of colitis mation of SPMs via the lipoxygenase routes involved in the (13, 24–26). Moreover, RvE1 and RvD1 have been recently biosynthesis of specific SPMs. The biosynthesis of SPM has implicated in the alleviation of inflammatory pain (27). Thus, recently been reviewed in detail and those interested should the potential therapeutic benefits of SPMs are far-reaching. see Ref. 12. Much recent attention has been paid to understanding the innate mechanisms involved in the resolution of inflamma- Active resolution: biosynthesis of SPM tion at mucosal sites. The best understood are the families of Resolution of acute, self-limited inflammation is distinct, by lipid mediators termed the resolvins and the maresins (2). Re- definition, from anti-inflammatory process (3). Proresolving solvins have been studied in most detail and are v-3 PUFA- mediators restrict further infiltration of polymorphonuclear derived lipid mediators central to activation of the inflamma- leukocyte (PMN, neutrophil) to sites of acute inflammation tory resolution program (2, 3). The discovery of resolvins was and promote resolution via enhancing clearance of apoptotic permitted by using an unbiased systems approach to acute cells by (3). Importantly, proresolving mediators contained self-limited/naturally resolving inflammatory exu- stimulate antimicrobial activities of epithelia (13, 14), aiding dates using liquid chromatography-mass spectrometry-mass a return to tissue homeostasis. These are particularly relevant spectrometry–based lipidemics and earlier knowledge that in the eye, lung, and oral epithelial surfaces. For example, v-3 PUFAs are beneficial to a number of cardiovascular and RvE1 reduces ocular herpes simplex-induced inflammation immunoregulatory responses (9). Ensuing studies revealed the (15); protectin D1 reduces ocular epithelial injury (16); existence of novel families of lipid mediators, derived from resolvin D1 (RvD1), RvE1, and protectin D1 each reduce either EPA (C20:5, 18-series resolvins), as well as DHA (C22:6, airway inflammation (17–20); and RvE1 reduces oral in- 17-series resolvins), which potently and stereoselectively ini- The Journal of Immunology 3477 tiate and enhance the resolution mechanisms in acute inflam- houses the mucosal (38), and defects in these mation. defensive functions contribute to disease pathogenesis (e.g., loss of function in mucin-2/Paneth cells can contribute to Mechanisms of SPM-mediated resolution inflammatory bowel disease) (39). Concordantly, antimicro- To date, an array of SPMs has been identified with potent bial generation provides protection for other mucosal proresolution activities; their mechanisms of action are equally epithelial surfaces: lung epithelia produce defensins and LL- diverse. ATL (15-epi-lipoxin) binds to the lipoxin A4 (LXA4) 37 (40), corneal and conjunctival epithelia express LL-37 (ALX/FPR2; 2), eliciting (41), and oral epithelia are protected by antimicrobial pep- antagonistic activities on PMN (28). RvE1 binds to tides secreted in saliva (42, 43). and interacts with ChemR23 receptor, resulting in ERK and Like many aspects of immunology, the view that the epi- AKT and subsequent signal transduction via thelium is merely a physical selective barrier has changed. The ribosomal protein S6 to enhance epithelium is now viewed as an active player in normal ho- (29). RvE1 also binds to the LTB4 receptor BLT1 on neu- meostatic mechanisms of mucosal immunity, and in some trophils, where it acts as a partial agonist (30). Aside from sig- instances, the epithelium may centrally orchestrate mucosal nal transduction directly affecting leukocyte function, modu- innate immunity and inflammation (44). lation of gene expression in response to SPM has revealed key “Classical” antimicrobial peptides insight to their mechanism of resolution. LXA4 and RvE1 in- duce CCR5 expression on the surface of apoptotic PMN and The classically viewed antimicrobial peptides represent a di- Downloaded from T cells, resulting in sequestration of CCL3/CCL5 in murine verse array of small peptides (12–50 aa), containing a positive peritonitis, facilitating resolution (31). RvE1 and RvD1 both charge and an amphipathic structure. The most studied an- attenuate PMN transmigration across endothelia (32, 33). timicrobial peptides to date are cathelicidins and defensins. Furthermore, RvE1 accelerates the clearance apically adherent Cathelicidin (LL-37) is expressed by epithelial cells, neu- PMN from epithelia by enhancing antiadhesive CD55 ex- trophils, , and macrophages, and can stimulate che- pression (22). Likewise, ATL induces the expression of an motaxis via the ALX/FPR2 receptor on these cells (45). http://www.jimmunol.org/ antimicrobial peptide, bactericidal-permeability enhancing, in Posttranslational processing is essential for its antimicrobial epithelial cells (14). Also, resolvin D2 (7S,8R,17S-trihydroxy- activity in vivo (46) and is accomplished by serine proteases 4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) enhances phago- such as kallikreins (47) or PMN proteases such as proteinase-3 cyte killing of microbes, improving survival in cecal ligation (48). LL-37 antimicrobial activity was originally thought puncture-initiated sepsis (34), and RvD1 modulates macro- to neutralize endotoxin because of its cationic/amphipathic phage responses to LPS-TLR4 signaling, resulting in decreased capacities to interact with anionic LPS or prevent LPS bind- proinflammatory release, whereas maintaining IL-10 ing to CD14 (49). Aside from preventing sepsis by interfering

expression (35). with the ability of LPS to stimulate TLR4 signaling, LL-37 by guest on September 28, 2021 More recently, RvE1 was discovered to upregulate the ex- have subsequently been demonstrated to directly dampen proin- pression of intestinal alkaline phosphatase (ALPI), a marker flammatory signaling initiated by LPS (50). Mice deficient in of differentiation with a surprising role in maintenance of the only known murine cathelicidin (encoded by the gene bacterial homeostasis (13). Given the proximity of mucosal Cnlp) show significant increases in susceptibility to a number of surfaces to bacterial Ags and the vital role of antimicrobial mucosal infections (51). peptides in host defense, we will discuss the potential role for Defensins are cationic antimicrobial peptides broadly classed antimicrobial peptides in the process of resolution. as a-andb-defensins, the former predominantly expressed by PMN and Paneth cells, and the latter by epithelia (52). Similar Antimicrobial peptides in the mucosa to LL-37s, a-defensins are activated by proteolytic processing Epithelial cells are uniquely positioned to serve as a direct line of an inactive precursor (53) and are stored in granules of of communication between the immune system and the ex- PMN. In contrast with a-defensins, b-defensins typically have ternal environment. In their normal state, mucosal surfaces short N-terminal extensions, and all possess some measure of are exposed on the lumenal surface to high concentrations antimicrobial activity in their full-length forms. Defensins have of foreign Ags, whereas at the same time, they are intimately broad antimicrobial actions on Gram-positive and -negative associated with the immune system via subepithelial lymphoid , and defects in defensin expression have been shown to tissue (36). Polarized epithelia form a physical selective barrier contribute to a number of mucosal inflammatory diseases, in- to allow absorption/secretion whereas preventing entry of cluding inflammatory bowel disease and necrotizing enteroco- into the body. The mucosal epithelium comprises litis (54). b-Defensins are secreted in saliva and are thought to a heterogeneous population of differentiated epithelia with be protective against periodontitis and caries (43). Mutations of distinct functions: absorptive enterocytes, mucus-secreting the 39-untranslated region of b-defensin lead to chronic and goblet cells, antimicrobial peptide-secreting Paneth cells, and aggressive periodontitis (55). enteroendocrine cells (37). Immunomodulatory functions of antimicrobial peptides. Given their Antimicrobial peptides are secreted prophylactically by the name, antimicrobial peptides were originally thought to func- epithelium into the viscous mucus layer, thus minimizing the tion merely as “natural antibiotics,” specialized in the killing of instance of epithelium-adhering bacteria. Similarly, Paneth bacteria. This bias has hampered discovery of their diverse array cells secrete antimicrobial peptides (defensins/lectins) main- of function in immunity and their regulation in host defense. taining intestinal crypt sterility. Consequently, the epithelium Increasing evidence indicates that aside from their antimicrobial forms an important barrier, preventing the free mixing of activity, antimicrobial peptides can modulate immune responses lumenal antigenic material with the lamina propria, which by inducing cytokine/ production, inhibiting LPS- 3478 BRIEF REVIEWS: ANTIMICROBIALS AND INFLAMMATORY RESOLUTION induced proinflammatory cytokine production, promoting neutralization of bacterial LPS (endotoxin), as well as serving , and modulating the responses of dendritic as an opsonin for phagocytosis of Gram-negative bacteria by cells or T cells. As such, antimicrobial peptides may be viewed (70, 71). The high affinity of BPI for the lipid A as bridging the gap between innate and adaptive immunity. region of LPS (72) targets its cytotoxic activity to Gram- Cathelicidin has immunomodulatory functions; for instance, negative bacteria. Binding of BPI to the Gram-negative bac- it is chemotactic to mast cells and PMN via interaction with the terial outer membrane is followed by a time-dependent pene- ALX/FPR2 receptor (45, 56), which is blocked by the anti- tration of the molecule to the bacterial inner membrane where inflammatory LXA4 stable analog. Cathelicidin stimulates re- damage results in loss of membrane integrity, dissipation of lease of the anti-inflammatory PGD2 from mast cells (57), electrochemical gradients, and bacterial death (73). BPI binds which as mentioned earlier can prime tissues for resolution by the lipid A region of LPS with high affinity (74, 75), and expressing enzymes necessary for resolution. Human b-defen- thereby prevents its interaction with other (proinflammatory) sin 2 also possesses immunomodulatory functions and, like LL- LPS-binding molecules, including LBP and CD14 (76). Be- 37, is known to be chemotactic for mast cells and activated cause BPI binds the lipid A region common to all LPSs, it is b PMN (58). -Defensin 3 upregulates COX-2 and PGE2 bio- able to neutralize endotoxin from a broad array of Gram- synthesis in gingival fibroblasts (59). b-Defensins antagonize negative pathogens (71). The selective and potent action of T cell tissue infiltration and promote exfiltration (60, 61). BPI against Gram-negative bacteria and their LPS is fully Considering their rapid release in response to “danger signals” manifest in biologic fluids, including plasma, serum, and whole and their consequent immunomodulatory activities has led to blood (71, 77). In multiple animal models of Gram-negative Downloaded from the concept that antimicrobial peptides can act as early warning sepsis and/or endotoxemia, administration of BPI congeners signals for infection and the creation of term alarmins (62). is associated with improved outcome (78, 79). These studies in Antimicrobial peptides and restitution/wound closure. As part of epithelia have identified a previously unappreciated “molecular their proresolving activity, both LL-37 (63, 64) and b-defensin shield” for protection of mucosal surfaces against Gram- 2 (65) are known to promote epithelial , neces- negative bacteria and their endotoxin. sary for mucosal restitution after physical injury or damage ALPI. There is much recent interest in ALPI, a 70-kDa, GPI- http://www.jimmunol.org/ from immune activity. Human b-defensin 2 stimulates migra- anchored protein expressed on the apical (luminal) aspect of tion and proliferation and tube formation of endothelial intestinal epithelial cell (80). In the past, this molecule had been cells in wounds, resulting in neovascularization and accelerated viewed as one of the better epithelial differentiation markers, wound healing (66). LL-37 has been proposed to initiate with little understanding of the true function of this molecule tissue remodeling via matrix metalloproteinase activity and within the mucosa. More recent studies have identified this promote wound closure via induction of the Snail/Slug molecule as a central player in microbial homeostasis (81–83). transcription factors, necessary for E-cadherin transcription A recent microarray screento identifyRvE1-regulated genes in and epithelial adherens junction formation (64). intestinal epithelial cells revealed two important findings. First, by guest on September 28, 2021 these studies revealed the previously unappreciated native ex- “Nonclassical” antimicrobial peptides pression of the RvE1 receptor ChemR23 on epithelial cells. A Bactericidal permeability-increasing protein. A number of addi- screen of various epithelial cell lines revealed prominent ex- tional mechanisms exist to maintain homeostasis at mucosal pression of ChemR23 on human intestinal epithelial cell lines surfaces. Among the innate antimicrobial defense molecules (T84 and Caco-2). Unique was the pattern of expression on of humans is bactericidal permeability-increasing protein polarized epithelia. This analysis revealed that ChemR23 (BPI), a 55- to 60-kDa protein originally found in neutro- localizes predominantly to the apical membrane surface, which phil azurophilic granules, on the neutrophil cell surface and, was somewhat unexpected given that most other - to a lesser extent, in specific granules of (67). coupled receptors exhibit basolateral expression in polarized Subsequently, BPI was found to be expressed in epithelial epithelia (84). Such membrane distribution of ChemR23 sug- cells (14). Based on an original transcriptional profiling ap- gested that the localized generation of RvE1 during PMN– proach to identify novel ATL-regulated genes in intestinal epithelial interactions could occur at the apical (lumenal) aspect epithelial cells, BPI was found to be expressed in both human of the tissue. This is an intriguing possibility given that the and murine epithelial cells of wide origin (oral, pulmonary, and other known function for RvE1 on mucosal epithelia is to gastrointestinal mucosa), and each was similarly regulated by promote the termination and clearance of PMN after trans- ATL. Functional studies using a BPI-neutralizing antiserum migration (22), through well-characterized, CD55-dependent revealed that surface-localized BPI blocks endotoxin-mediated mechanisms (85, 86). Thus, the PMN–epithelial interactions signaling in epithelia and kills Salmonella typhimurium. More that occur within the lumen of the intestine may initiate a recently, molecular studies revealed that epithelial BPI is proresolving signature to the epithelium during PMN transit selectively induced by ATL and prominently regulated by the through the mucosa. transcription factors Sp1/3 and C/EBPb (68). Additional Second, these microarray studies identified a prominent studies in human and murine tissue ex vivo revealed that BPI RvE1-dependent antimicrobial signature within the epithe- is diffusely expressed along the crypt-villous axis (14, 68), and lium, including the induction of BPI and the BPI-like mol- that epithelial BPI protein levels decrease along the length ecule PLUNC (palate, lung, nasal epithelium clone) (13). Also of the intestine (69). More recent studies with SPM have re- notable was the induction of epithelial ALPI by RvE1. vealed the expression of BPI in various mucosal epithelia (67). Surface-expressed ALPI was shown to retard Gram-negative As its name infers, BPI selectively exerts multiple antimi- bacterial growth and to potently neutralize LPS through crobial actions against Gram-negative bacteria, including cy- a mechanism involving dephosphorylation of 1,49-bisphos- totoxicity through damage to bacterial inner/outer membranes, phorylated glucosamine disaccharide of LPS lipid A (82, 83). The Journal of Immunology 3479

FIGURE 2. RvE1 biosynthesis and model for induction of epithelial ALPI. A, De novo synthesis of RvE1 at the mucosal surface. During epithelial cell– PMN interactions, RvE1 production is amplified by transcellular biosynthesis via the interactions of two or more cell types, each contributing an enzymatic product. In the example shown here, epithelial cell COX-2 generates 18- HEPE from dietary EPA and PMN- expressed 5-lipoxygenase (5-LO), and lta4H then generates RvE1 (see Refs. 34 and 88 for further details). Such locally generated RvE1 is then made available to activate apically expressed ChemR23, which, in turn, induces the expression of 3 ALPI. Original magnification 200. B, Downloaded from Induction of ALPI activity after in vivo administration of RvE1 during the res- olution of inflammation of a mouse model of dextran sodium sulfate (DSS) colitis [see Campbell et al. (13)]. Origi- nal magnification 3400. http://www.jimmunol.org/

This observation was translated to the murine model dextran Conclusions sodium sulfate colitis and revealed that induction of ALPI by Given the close proximity of bacteria to mucosal surfaces, RvE1 in vivo strongly correlated with the resolution phase of maintenance of tissue homeostasis presents a significant chal- inflammation (Fig. 2). Moreover, inhibition of ALPI activity lenge. After successful handling of infiltrating bacteria, the was shown to increase the severity of colitic disease and ab- generation of proresolving mediators accelerates the return to by guest on September 28, 2021 rogate the protective influences of RvE1 (13). Like those homeostasis. This review highlights not only the multifunc- defining epithelial expression of BPI (14), these studies pro- tional role of antimicrobial peptides in inflammation, but also vide an example of the critical interface between inflammatory the interdependent relationship between the induction of resolution and the importance of antimicrobial mechanisms. antimicrobial peptides and the initiation of resolution path-

FIGURE 3. Temporal regulation and multifunctional roles of SPM-regulated antimicrobial peptides in the resolution of inflammation. After microbial detection, classical antimicrobial peptides are released by epithelial cells and recruited immune cells. Antimicrobial peptides aid in the killing of bacteria, stimulating PMNs to generate reactive species (with inadvertent tissue damage), and promote further release of antimicrobial peptides and proinflammatory and anti-in- flammatory lipid mediators via COX-2 induction and acetylation. In the resolution phase, generation of SPM elicits the induction of “nonclassical” antimicrobial peptides such as ALPI and BPI (13, 14), which accelerate return to homeostasis via continued bacterial killing, and inhibition of LPS signaling (35). Furthermore, SPMs can block and/or counteract the release of “classical” antimicrobial peptides from leukocytes, dampening the “Alarmin” signals (45). 3480 BRIEF REVIEWS: ANTIMICROBIALS AND INFLAMMATORY RESOLUTION ways and the role of resolvins in this process (see Fig. 3). After 10. Cla`ria, J., and C. N. Serhan. 1995. Aspirin triggers previously undescribed bioactive by human endothelial cell-leukocyte interactions. Proc. Natl. Acad. Sci. microbial detection, “alarmins” or “classical” antimicrobial USA 92: 9475–9479. peptides are released by infiltrating immune cells, aiding the 11. Serhan, C. N., J. F. Maddox, N. A. Petasis, I. Akritopoulou-Zanze, A. Papayianni, H. R. Brady, S. P. Colgan, and J. L. Madara. 1995. Design of lipoxin A4 stable killing of bacteria, stimulating neutrophils to generate reactive analogs that block transmigration and adhesion of human neutrophils. Biochemistry oxygen species (with inadvertent tissue damage), promoting 34: 14609–14615. further release of antimicrobial peptides, and releasing both 12. Bannenberg, G., and C. N. Serhan. 2010. Specialized pro-resolving lipid mediators in the inflammatory response: an update. Biochim. Biophys. Acta 1801: 1260–1273. proinflammatory and anti-inflammatory lipids via COX-2 13. Campbell, E. L., C. F. MacManus, D. J. Kominsky, S. Keely, L. E. Glover, induction. As such, “classical” antimicrobial peptides could B. E. Bowers, M. Scully, W. J. Bruyninckx, and S. P. Colgan. 2010. Resolvin E1- induced intestinal alkaline phosphatase promotes resolution of inflammation be considered to have both proinflammatory and anti- through LPS detoxification. Proc. Natl. Acad. Sci. USA 107: 14298–14303. inflammatory properties, suggesting that antimicrobial pep- 14. Canny, G., O. Levy, G. T. Furuta, S. Narravula-Alipati, R. B. Sisson, C. N. Serhan, tides prime the inflammatory microenvironment of the and S. P. Colgan. 2002. Lipid mediator-induced expression of bactericidal/ permeability-increasing protein (BPI) in human mucosal epithelia. Proc. Natl. mucosal surface for resolution. After generation of SPM, Acad. Sci. USA 99: 3902–3907. “nonclassical” antimicrobial peptides may accelerate return to 15. Rajasagi, N. K., P. B. Reddy, A. Suryawanshi, S. Mulik, P. Gjorstrup, and B. T. Rouse. 2011. Controlling herpes simplex virus-induced ocular inflammatory homeostasis via continued bacterial killing, inhibition of LPS lesions with the lipid-derived mediator resolvin E1. J. Immunol. 186: 1735–1746. signaling, and inhibition of “classical” antimicrobial peptide 16. Gronert, K., N. Maheshwari, N. Khan, I. R. Hassan, M. Dunn, and M. Laniado Schwartzman. 2005. A role for the mouse 12/15-lipoxygenase pathway in promoting release from leukocytes. As such, it would appear that an epithelial wound healing and host defense. J. Biol. Chem. 280: 15267–15278. interdependent relationship exists between the activity of 17. Aoki, H., T. Hisada, T. Ishizuka, M. Utsugi, T. Kawata, Y. Shimizu, F. Okajima, K. Dobashi, and M. Mori. 2008. Resolvin E1 dampens airway inflammation and antimicrobial peptides and the initiation of resolution pro- Downloaded from hyperresponsiveness in a murine model of asthma. Biochem. Biophys. Res. Commun. grams. Along these lines, RvE1 blocks LTB4-stimulated re- 367: 509–515. 18. Haworth, O., M. Cernadas, R. Yang, C. N. Serhan, and B. D. Levy. 2008. Resolvin lease of LL-37 by human PMN, and LXA4 inhibits proin- E1 regulates 23, interferon-gamma and lipoxin A4 to promote the flammatory actions of LL-37 (45). resolution of allergic airway inflammation. Nat. Immunol. 9: 873–879. Overall, the contribution of microbes to health and disease 19. Levy, B. D., P. Kohli, K. Gotlinger, O. Haworth, S. Hong, S. Kazani, E. Israel, K. J. Haley, and C. N. Serhan. 2007. Protectin D1 is generated in asthma and has provided an elegant lesson in biology. Results from model dampens airway inflammation and hyperresponsiveness. J. Immunol. 178: 496–502. disease systems and humans allowed the discovery of pro- 20. Wang, B., X. Gong, J. Y. Wan, L. Zhang, Z. Zhang, H. Z. Li, and S. Min. 2011. http://www.jimmunol.org/ resolving mechanisms that are fundamental to our un- Resolvin D1 protects mice from LPS-induced acute lung injury. Pulm. Pharmacol. Ther. 24: 434–441. derstanding of disease pathogenesis. As summarized in this 21. Hasturk,H.,A.Kantarci,E.Goguet-Surmenian,A.Blackwood,C.Andry,C.N.Serhan, review, the interdependence of antimicrobial defense mecha- and T. E. Van Dyke. 2007. Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. J. Immunol. 179: 7021–7029. nisms with inflammatory disease resolution has provided an 22. Campbell, E. L., N. A. Louis, S. E. Tomassetti, G. O. Canny, M. Arita, informative example of how these biochemical pathways yield C. N. Serhan, and S. P. Colgan. 2007. Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution. FASEB J. 21: insight toward a better understanding of tissue function. 3162–3170. Ongoing studies of antimicrobial regulation in the mucosa, 23. Hasturk, H., A. Kantarci, T. Ohira, M. Arita, N. Ebrahimi, N. Chiang, N. A. Petasis, B. D. Levy, C. N. Serhan, and T. E. Van Dyke. 2006. RvE1 protects

exemplified by SPM-regulated BPI and ALPI in intestinal by guest on September 28, 2021 from local inflammation and osteoclast- mediated bone destruction in periodontitis. epithelia, should provide templates for the design of new and FASEB J. 20: 401–403. effective therapies for inflammatory disease resolution. 24. Arita, M., M. Yoshida, S. Hong, E. Tjonahen, J. N. Glickman, N. A. Petasis, R. S. Blumberg, and C. N. Serhan. 2005. Resolvin E1, an endogenous lipid me- diator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trini- trobenzene sulfonic acid-induced colitis. Proc. Natl. Acad. Sci. USA 102: 7671– Disclosures 7676. S.P.C. and C.N.S. are inventors on patents assigned to Brigham and Women’s 25. Bento, A. F., R. F. Claudino, R. C. Dutra, R. Marcon, and J. B. Calixto. 2011. Hospital-Partners HealthCare on the composition, uses, and clinical develop- Omega-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin- ment of anti-inflammatory and proresolving mediators and related compounds. triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice. J. Immunol. 187: 1957–1969. The following are licensed for clinical development: lipoxins to Bayer Health- 26. Lima-Garcia, J., R. Dutra, K. da Silva, E. Motta, M. Campos, and J. Calixto. The Care and resolvins and related materials to Resolvyx Pharmaceuticals. C.N.S. precursor of resolvin D series and aspirin-triggered resolvin D1 display anti- retains founder stock in Resolvyx. E.L.C. has no financial conflicts of interest. hyperalgesic properties in adjuvant-induced in rats. Br. J. Pharmacol. In press. 27. Xu, Z. Z., L. Zhang, T. Liu, J. Y. Park, T. Berta, R. Yang, C. N. Serhan, and R. R. Ji. 2010. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and References peripheral actions. Nat. Med. 16: 592–597, 1p following 597. 28. Takano, T., S. Fiore, J. F. Maddox, H. R. Brady, N. A. Petasis, and C. N. Serhan. 1. Majno, G., and I. Joris. 1996. Cells, Tissues and Disease: Principles of General Pa- 1997. Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are thology. Blackwell Science, Cambridge, MA. potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. J. 2. Serhan, C. N., and N. Chiang. 2008. Endogenous pro-resolving and anti- Exp. Med. 185: 1693–1704. inflammatory lipid mediators: a new pharmacologic genus. Br. J. Pharmacol. 153 29. Ohira, T., M. Arita, K. Omori, A. Recchiuti, T. E. Van Dyke, and C. N. Serhan. (Suppl. 1): S200–S215. 2010. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. J. 3. Serhan, C. N., N. Chiang, and T. E. Van Dyke. 2008. Resolving inflammation: Biol. Chem. 285: 3451–3461. dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol. 8: 30. Arita, M., T. Ohira, Y. P. Sun, S. Elangovan, N. Chiang, and C. N. Serhan. 2007. 349–361. Resolvin E1 selectively interacts with B4 receptor BLT1 and ChemR23 4. Serhan, C. N., C. B. Clish, J. Brannon, S. P. Colgan, N. Chiang, and K. Gronert. to regulate inflammation. J. Immunol. 178: 3912–3917. 2000. Novel functional sets of lipid-derived mediators with antiinflammatory 31. Ariel, A., G. Fredman, Y. P. Sun, A. Kantarci, T. E. Van Dyke, A. D. Luster, and actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal C. N. Serhan. 2006. Apoptotic neutrophils and T cells sequester during antiinflammatory drugs and transcellular processing. J. Exp. Med. 192: 1197–1204. immune response resolution through modulation of CCR5 expression. Nat. 5. Bik, E. M. 2009. Composition and function of the human-associated microbiota. Immunol. 7: 1209–1216. Nutr. Rev. 67(Suppl. 2): S164–S171. 32. Serhan, C. N., S. Hong, K. Gronert, S. P. Colgan, P. R. Devchand, G. Mirick, and 6. Gilroy, D. W., P. R. Colville-Nash, D. Willis, J. Chivers, M. J. Paul-Clark, and R. L. Moussignac. 2002. Resolvins: a family of bioactive products of omega-3 fatty D. A. Willoughby. 1999. Inducible cyclooxygenase may have anti-inflammatory acid transformation circuits initiated by aspirin treatment that counter proin- properties. Nat. Med. 5: 698–701. flammation signals. J. Exp. Med. 196: 1025–1037. 7. Spite, M., and C. N. Serhan. 2010. Novel lipid mediators promote resolution of 33. Sun, Y. P., S. F. Oh, J. Uddin, R. Yang, K. Gotlinger, E. Campbell, S. P. Colgan, acute inflammation: impact of aspirin and statins. Circ. Res. 107: 1170–1184. N. A. Petasis, and C. N. Serhan. 2007. Resolvin D1 and its aspirin-triggered 17R 8. Schwab, J. M., N. Chiang, M. Arita, and C. N. Serhan. 2007. Resolvin E1 and epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic protectin D1 activate inflammation-resolution programmes. Nature 447: 869–874. inactivation. J. Biol. Chem. 282: 9323–9334. 9. Serhan, C. N., S. D. Brain, C. D. Buckley, D. W. Gilroy, C. Haslett, L. A. O’Neill, 34. Spite, M., L. V. Norling, L. Summers, R. Yang, D. Cooper, N. A. Petasis, M. Perretti, A. G. Rossi, and J. L. Wallace. 2007. Resolution of inflammation: state R. J. Flower, M. Perretti, and C. N. Serhan. 2009. Resolvin D2 is a potent regulator of the art, definitions and terms. FASEB J. 21: 325–332. of leukocytes and controls microbial sepsis. Nature 461: 1287–1291. The Journal of Immunology 3481

35. Palmer, C. D., C. J. Mancuso, J. P. Weiss, C. N. Serhan, E. C. Guinan, and 62. Oppenheim, J. J., and D. Yang. 2005. Alarmins: chemotactic activators of immune O. Levy. 17(R)-Resolvin D1 differentially regulates TLR4-mediated responses of responses. Curr. Opin. Immunol. 17: 359–365. primary human macrophages to purified LPS and live E. coli. J. Leukoc. Biol. In press. 63. Otte, J. M., A. E. Zdebik, S. Brand, A. M. Chromik, S. Strauss, F. Schmitz, 36. Beagley, K. W., and A. J. Husband. 1998. Intraepithelial : origins, L. Steinstraesser, and W. E. Schmidt. 2009. Effects of the cathelicidin LL-37 on distribution, and function. Crit. Rev. Immunol. 18: 237–254. intestinal epithelial barrier integrity. Regul. Pept. 156: 104–117. 37. Laukoetter, M. G., P. Nava, and A. Nusrat. 2008. Role of the intestinal barrier in 64. Carretero, M., M. J. Esca´mez, M. Garcı´a, B. Duarte, A. Holguı´n, L. Retamosa, inflammatory bowel disease. World J. Gastroenterol. 14: 401–407. J. L. Jorcano, M. D. Rı´o, and F. Larcher. 2008. In vitro and in vivo wound healing- 38. McCole, D. F., and K. E. Barrett. 2007. Varied role of the gut epithelium in promoting activities of human cathelicidin LL-37. J. Invest. Dermatol. 128: 223–236. mucosal homeostasis. Curr. Opin. Gastroenterol. 23: 647–654. 65. Otte, J. M., I. Werner, S. Brand, A. M. Chromik, F. Schmitz, M. Kleine, and 39. Kim, Y. S., and S. B. Ho. 2010. Intestinal goblet cells and mucins in health and W. E. Schmidt. 2008. Human 2 promotes intestinal wound healing in disease: recent insights and progress. Curr. Gastroenterol. Rep. 12: 319–330. vitro. J. Cell. Biochem. 104: 2286–2297. 40. Singh, P. K., H. P. Jia, K. Wiles, J. Hesselberth, L. Liu, B. A. Conway, 66. Baroni, A., G. Donnarumma, I. Paoletti, I. Longanesi-Cattani, K. Bifulco, E. P. Greenberg, E. V. Valore, M. J. Welsh, T. Ganz, et al. 1998. Production of beta- M. A. Tufano, and M. V. Carriero. 2009. Antimicrobial human beta-defensin-2 defensins by human airway epithelia. Proc. Natl. Acad. Sci. USA 95: 14961–14966. stimulates migration, proliferation and tube formation of human umbilical vein 41. Gordon, Y. J., L. C. Huang, E. G. Romanowski, K. A. Yates, R. J. Proske, and endothelial cells. Peptides 30: 267–272. A. M. McDermott. 2005. Human cathelicidin (LL-37), a multifunctional peptide, 67. Canny, G., and O. Levy. 2008. Bactericidal/permeability-increasing protein (BPI) is expressed by ocular surface epithelia and has potent antibacterial and antiviral and BPI homologs at mucosal sites. Trends Immunol. 29: 541–547. activity. Curr. Eye Res. 30: 385–394. 68. Canny, G., E. Cario, A. Lennartsson, U. Gullberg, C. Brennan, O. Levy, and 42. Sahasrabudhe, K. S., J. R. Kimball, T. H. Morton, A. Weinberg, and B. A. Dale. S. P. Colgan. 2006. Functional and biochemical characterization of epithelial 2000. Expression of the antimicrobial peptide, human beta-defensin 1, in duct cells bactericidal/permeability-increasing protein. Am. J. Physiol. Gastrointest. Liver of minor salivary glands and detection in saliva. J. Dent. Res. 79: 1669–1674. Physiol. 290: G557–G567. 43. Abiko, Y., M. Nishimura, and T. Kaku. 2003. Defensins in saliva and the salivary 69. Canny, G. O., R. T. Trifonova, D. W. Kindelberger, S. P. Colgan, and glands. Med. Electron Microsc. 36: 247–252. R. N. Fichorova. 2006. Expression and function of bactericidal/permeability- 44. Shale, M., and S. Ghosh. 2009. How intestinal epithelial cells tolerise dendritic cells increasing protein in human genital tract epithelial cells. J. Infect. Dis. 194: 498– and its relevance to inflammatory bowel disease. Gut 58: 1291–1299. 502. 45. Wan, M., C. Godson, P. J. Guiry, B. Agerberth, and J. Z. Haeggstro¨m. 2011. 70. Elsbach, P., and J. Weiss. 1998. Role of the bactericidal/permeability-increasing Downloaded from /antimicrobial peptide LL-37 proinflammatory circuits are mediated protein in host defence. Curr. Opin. Immunol. 10: 45–49. by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1. 71. Levy, O. 2000. A neutrophil-derived anti-infective molecule: bactericidal/perme- FASEB J. 25: 1697–1705. ability-increasing protein. Antimicrob. Agents Chemother. 44: 2925–2931. 46. Cole, A. M., J. Shi, A. Ceccarelli, Y. H. Kim, A. Park, and T. Ganz. 2001. In- 72. Gazzano-Santoro, H., J. B. Parent, L. Grinna, A. Horwitz, T. Parsons, G. Theofan, hibition of neutrophil elastase prevents cathelicidin activation and impairs clearance P. Elsbach, J. Weiss, and P. J. Conlon. 1992. High-affinity binding of the of bacteria from wounds. Blood 97: 297–304. bactericidal/permeability-increasing protein and a recombinant amino-terminal 47. Yamasaki, K., J. Schauber, A. Coda, H. Lin, R. A. Dorschner, N. M. Schechter, fragment to the lipid A region of lipopolysaccharide. Infect. Immun. 60: 4754–4761.

C. Bonnart, P. Descargues, A. Hovnanian, and R. L. Gallo. 2006. Kallikrein- 73. Mannion, B. A., J. Weiss, and P. Elsbach. 1990. Separation of sublethal and lethal http://www.jimmunol.org/ mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. effects of the bactericidal/permeability increasing protein on . J. Clin. FASEB J. 20: 2068–2080. Invest. 85: 853–860. 48. Sørensen, O., K. Arnljots, J. B. Cowland, D. F. Bainton, and N. Borregaard. 1997. The 74. Levy, O., C. E. Ooi, P. Elsbach, M. E. Doerfler, R. I. Lehrer, and J. Weiss. 1995. human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and meta- Antibacterial proteins of differ in interaction with endotoxin. Com- myelocytes and localized to specific granules in neutrophils. Blood 90: 2796–2803. parison of bactericidal/permeability-increasing protein, p15s, and defensins. J. 49. Rosenfeld, Y., N. Papo, and Y. Shai. 2006. Endotoxin (lipopolysaccharide) neu- Immunol. 154: 5403–5410. tralization by innate immunity host-defense peptides. Peptide properties and 75. Ulevitch, R. J., and P. S. Tobias. 1999. Recognition of gram-negative bacteria and plausible modes of action. J. Biol. Chem. 281: 1636–1643. endotoxin by the . Curr. Opin. Immunol. 11: 19–22. 50. Mookherjee, N., K. L. Brown, D. M. Bowdish, S. Doria, R. Falsafi, K. Hokamp, 76. Gazzano-Santoro, H., K. Me´sza´ros, C. Birr, S. F. Carroll, G. Theofan, F. M. Roche, R. Mu, G. H. Doho, J. Pistolic, et al. 2006. Modulation of the TLR- A. H. Horwitz, E. Lim, S. Aberle, H. Kasler, and J. B. Parent. 1994. Competition mediated inflammatory response by the endogenous human host defense peptide between rBPI23, a recombinant fragment of bactericidal/permeability-increasing

LL-37. J. Immunol. 176: 2455–2464. protein, and lipopolysaccharide (LPS)-binding protein for binding to LPS and by guest on September 28, 2021 51. Iimura, M., R. L. Gallo, K. Hase, Y. Miyamoto, L. Eckmann, and M. F. Kagnoff. gram-negative bacteria. Infect. Immun. 62: 1185–1191. 2005. Cathelicidin mediates innate intestinal defense against colonization with 77. Weiss, J., P. Elsbach, I. Olsson, and H. Odeberg. 1978. Purification and charac- epithelial adherent bacterial pathogens. J. Immunol. 174: 4901–4907. terization of a potent bactericidal and membrane active protein from the granules of 52. van Wetering, S., P. J. Sterk, K. F. Rabe, and P. S. Hiemstra. 1999. Defensins: key human polymorphonuclear leukocytes. J. Biol. Chem. 253: 2664–2672. players or bystanders in infection, injury, and repair in the lung? J. Clin. 78. Evans, T. J., A. Carpenter, D. Moyes, R. Martin, and J. Cohen. 1995. Protective Immunol. 104: 1131–1138. effects of a recombinant amino-terminal fragment of human bactericidal/ 53. Wilson, C. L., A. J. Ouellette, D. P. Satchell, T. Ayabe, Y. S. Lo´pez-Boado, permeability-increasing protein in an animal model of gram-negative sepsis. J. In- J. L. Stratman, S. J. Hultgren, L. M. Matrisian, and W. C. Parks. 1999. Regulation fect. Dis. 171: 153–160. of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate 79. Lin, Y., W. J. Leach, and W. S. Ammons. 1996. Synergistic effect of a recombinant host defense. Science 286: 113–117. N-terminal fragment of bactericidal/permeability-increasing protein and cefa- 54. Salzman, N. H., M. A. Underwood, and C. L. Bevins. 2007. Paneth cells, defensins, mandole in treatment of rabbit gram-negative sepsis. Antimicrob. Agents Chemother. and the commensal microbiota: a hypothesis on intimate interplay at the intestinal 40: 65–69. mucosa. Semin. Immunol. 19:70–83. Epub 20May 07, 2007. 80. Vaishnava, S., and L. V. Hooper. 2007. Alkaline phosphatase: keeping the peace at 55. Schaefer, A. S., G. M. Richter, M. Nothnagel, M. L. Laine, A. Ru¨hling, C. Scha¨fer, the gut epithelial surface. Cell Host Microbe 2: 365–367. N. Cordes, B. Noack, M. Folwaczny, J. Glas, et al. 2010. A 39 UTR transition within 81. Goldberg, R. F., W. G. Austen, Jr., X. Zhang, G. Munene, G. Mostafa, S. Biswas, DEFB1 is associated with chronic and aggressive periodontitis. Genes Immun. 11: 45–54. M. McCormack, K. R. Eberlin, J. T. Nguyen, H. S. Tatlidede, et al. 2008. In- 56. De Yang, Q. Chen, A. P. Schmidt, G. M. Anderson, J. M. Wang, J. Wooters, testinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral J. J. Oppenheim, and O. Chertov. 2000. LL-37, the neutrophil granule- and epi- nutrition. Proc. Natl. Acad. Sci. USA 105: 3551–3556. thelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as 82. Mata-Haro, V., C. Cekic, M. Martin, P. M. Chilton, C. R. Casella, and a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T. C. Mitchell. 2007. The vaccine adjuvant monophosphoryl lipid A as a TRIF- T cells. J. Exp. Med. 192: 1069–1074. biased agonist of TLR4. Science 316: 1628–1632. 57. Niyonsaba, F., M. Hirata, H. Ogawa, and I. Nagaoka. 2003. Epithelial cell-derived 83. Moyle, P. M., and I. Toth. 2008. Self-adjuvanting lipopeptide vaccines. Curr. Med. antibacterial peptides human beta-defensins and cathelicidin: multifunctional ac- Chem. 15: 506–516. tivities on mast cells. Curr. Drug Targets Inflamm. Allergy 2: 224–231. 84. Wozniak, M., J. R. Keefer, C. Saunders, and L. E. Limbird. 1997. Differential 58. Niyonsaba, F., K. Iwabuchi, H. Matsuda, H. Ogawa, and I. Nagaoka. 2002. Epi- targeting and retention of G protein-coupled receptors in polarized epithelial cells. J. thelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells Recept. Signal Transduct. Res. 17: 373–383. through a -sensitive and phospholipase C-dependent pathway. Int. 85. Lawrence, D. W., W. J. Bruyninckx, N. A. Louis, D. M. Lublin, G. L. Stahl, Immunol. 14: 421–426. C. A. Parkos, and S. P. Colgan. 2003. Antiadhesive role of apical decay-accelerating 59. Chotjumlong, P., S. Khongkhunthian, S. Ongchai, V. Reutrakul, and factor (CD55) in human neutrophil transmigration across mucosal epithelia. J. Exp. S. Krisanaprakornkit. 2010. Human beta-defensin-3 up-regulates cyclooxygenase-2 Med. 198: 999–1010. expression and prostaglandin E2 synthesis in human gingival fibroblasts. J. Peri- 86. Louis, N. A., K. E. Hamilton, T. Kong, and S. P. Colgan. 2005. HIF-dependent odontal Res. 45: 464–470. induction of apical CD55 coordinates epithelial clearance of neutrophils. FASEB J. 60. Feng, Z., G. R. Dubyak, M. M. Lederman, and A. Weinberg. 2006. Cutting edge: 19: 950–959. human beta defensin 3—a novel antagonist of the HIV-1 coreceptor CXCR4. J. 87. Serhan, C. N. 2007. Resolution phase of inflammation: novel endogenous anti- Immunol. 177: 782–786. inflammatory and proresolving lipid mediators and pathways. Annu. Rev. Immunol. 61. Ghannam, S., C. Dejou, N. Pedretti, J. P. Giot, K. Dorgham, H. Boukhaddaoui, 25: 101–137. V. Deleuze, F. X. Bernard, C. Jorgensen, H. Yssel, and J. Pe`ne. 2011. CCL20 and 88. Oh, S. F., P. S. Pillai, A. Recchiuti, R. Yang, and C. N. Serhan. 2011. Pro-resolving b-defensin-2 induce arrest of human Th17 cells on inflamed in vitro actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes under flow conditions. J. Immunol. 186: 1411–1420. and murine inflammation. J. Clin. Invest. 121: 569–581.