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The Essential Role of during with the Intracellular Bacterial

This information is current as Alexandra R. Witter, Busola M. Okunnu and Rance E. Berg of September 28, 2021. J Immunol 2016; 197:1557-1565; ; doi: 10.4049/jimmunol.1600599 http://www.jimmunol.org/content/197/5/1557 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

The Essential Role of Neutrophils during Infection with the Intracellular Bacterial Pathogen Listeria monocytogenes Alexandra R. Witter, Busola M. Okunnu, and Rance E. Berg Neutrophils have historically been characterized as first tion. It has been shown that these neutrophils are phagocytosed responder cells vital to host survival because of their by resident and dendritic cells in the liver, which ability to contain and eliminate bacterial and fungal could potentially induce a feedback loop that decreases further . However, recent studies have shown that (3). Alternately, the receptor CXCR4 neutrophils participate in both protective and detrimen- is upregulated as circulating neutrophils age, leading to traf- fickingbacktothebonemarrowwheretheyareingestedby tal responses to a diverse array of inflammatory and Downloaded from infectious diseases. Although the contribution of neu- macrophages (4–6). Although production is consti- trophils to extracellular has been investi- tutive during homeostasis, an enhanced neutrophil response is gated for decades, their specific role during intracellular often essential for host survival. bacterial infections has only recently been appreciated. Neutrophils in disease During infection with the Gram-positive intracellular

pathogen Listeria monocytogenes, neutrophils are recruited Neutrophils have a well-established role during fungal and http://www.jimmunol.org/ from the to sites of infection where they extracellular bacterial infections where they promote bacterial use novel bacterial-sensing pathways leading to phago- clearance through , production of ROS and re- and production of bactericidal factors. This re- active nitrogen species (RNS), neutrophil extracellular trap view summarizes the requirement of neutrophils during formation, and production of proinflammatory (6, 7). Recently, studies have focused on more nontraditional L. monocytogenes infection by examining both neutro- roles for neutrophils in disease including detrimental effects phil trafficking and function during primary and during inflammatory conditions, ranging from seasonal al- secondary infection. The Journal of Immunology, 2016, lergies to diabetes, protection against viral infections, and 197: 1557–1565. both protective and damaging effects during cancer (8). by guest on September 28, 2021 However, recent studies also suggest that neutrophils play an eutrophils are hematopoietic-derived immune cells important protective role during some intracellular bacterial that are generated, and continue to develop, in the infections, including L. monocytogenes. N bone marrow until recruited into circulation and then to sites of infection or inflammation. Steady-state neutrophil L. monocytogenes granulopoiesis is modulated by common stem cytokines, L. monocytogenes is a Gram-positive bacterium with a primarily such as IL-3 and IL-6, as well as G-CSF and GM-CSF. Under intracellular life cycle after infecting a host organism. L. mon- infectious or inflammatory conditions, neutrophil granulopoiesis ocytogenes infection occurs after ingestion of contaminated can be increased, typically termed “emergency granulopoiesis,” foods and is the third leading cause of death among foodborne to restore homeostasis in the bone marrow after recruitment of pathogens (9). Immunocompromised individuals, pregnant neutrophils to peripheral sites (1). Although IL-3, IL-6, G-CSF, women, and newborns are particularly susceptible to infection, and GM-CSF have all been shown to contribute to emergency which can result in septicemia, , and loss of fetus. granulopoiesis, it has also been demonstrated that the production Although foci of infection are generally established in the of (ROS) by bone marrow myeloid cells spleen and liver, L. monocytogenes can travel through the cir- is critical for this process during infection (2). Neutrophils that culation to the heart, the brain, and the bone marrow (10–12). traffic into tissues in the absence of infection or inflammation L. monocytogenes is able to cross the intestinal wall by binding commonly become apoptotic rather than returning to circula- to E-cadherin with one of its virulence factors, Internalin A.

Department of Cell and Immunology, University of North Texas Health Abbreviations used in this article: ecSOD, extracellular dismutase; FPR, Science Center, Fort Worth, TX 76107 formylated peptide receptor; H2O2, hydrogen peroxide; iNOS, inducible NO synthase; KO, knockout; LLO, listeriolysin O; MMP8, matrix metalloproteinase-8; NLR, Nod- ORCID: 0000-0002-2934-382X (R.E.B.). like receptor; NRROS, negative regulator of ROS; PAMP, pathogen-associated mo- Received for publication April 5, 2016. Accepted for publication June 16, 2016. lecular pattern; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, ; STIM1, stromal-interacting molecule 1. This work was supported by National Institutes of Health Grant AI109630 (to R.E.B.), a University of North Texas Health Science Center seed grant (to R.E.B.), and an American Ó Association of Immunologists Careers in Immunology Fellowship (to A.R.W. and R.E.B.). Copyright 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 Address correspondence and reprint requests to Dr. Rance E. Berg, Department of and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107. E-mail address: [email protected]

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600599 1558 BRIEF REVIEWS: NEUTROPHILS AND LISTERIA

From the intestine, L. monocytogenes disseminates through TNF-a and IL-12 in response to recognition of L. monocytogenes the lymphatics and the bloodstream to the spleen and liver, (32, 33). Inflammatory have been shown to respond where it can enter target cells via phagocytosis or induced to L. monocytogenes by producing IL-12 and IL-15 (34). Ad- endocytosis. In the liver, one of the primary target cells for ditional studies identified a differentiated population of CCR2+ infection is hepatocytes, which are initially directly infected inflammatory monocytes, also termed TNF-a/iNOS-producing through utilization of the virulence factor Internalin B binding dendritic cells (Tip-DCs), which are essential for clearance of to hepatocyte growth factor receptor (HGFR, Met, c-Met). L. monocytogenes infection (35). Ultimately, the production of Once internalized, L. monocytogenes is able to escape into the innate cytokines from macrophages and inflammatory mono- cytosol of host cells by secretion of listeriolysin O (LLO). cytes induces the production of IFN-g from multiple cell types, Cytoplasmic L. monocytogenes then replicates and spreads to leading to increased phagocytosis and killing of neighboring cells by polymerizing host with the aid of the (33, 36). The complex interplay between - actin-assembly–inducing protein A (13, 14). This indirect in- resident and recruited phagocytic cells is critical for protec- fection via cell-to-cell spread is effective, particularly in the tion of the host against L. monocytogenes. liver, because it allows L. monocytogenes to infect neighboring cells without being exposed to opsonization or recognition and Neutrophil recruitment during L. monocytogenes infection killing by innate immune cells. Neutrophil release from bone marrow. During homeostasis, neu- trophils are retained in the bone marrow by the interaction of

Requirement of neutrophils during L. monocytogenes infection CXCR4 with its ligand CXCL12 (SDF-1), which is expressed by Downloaded from Initial immune responses against L. monocytogenes are managed nonhematopoietic bone marrow cells. Post L. monocytogenes by innate immune cells, with macrophages, monocytes, and infection, neutrophils are rapidly recruited out of the bone neutrophils playing a central role. Early depletion studies using marrow primarily because of the downregulation of CXCR4 the anti–GR-1 mAb (RB6-8C5) concluded that neutrophils are followed by the upregulation of CXCR2, the receptor for critically important for host defense during L. monocytogenes neutrophil-attracting such as CXCL1 (KC) and infection (15–21). More recently, it was shown that the anti– CXCL2 (MIP-2a) (37, 38). Myeloid-lineage specific loss of http://www.jimmunol.org/ GR-1 Ab binds to Ly6G, which is expressed exclusively by CXCR4 was shown to lead to premature release of neutrophils neutrophils, and Ly6C, which is expressed by neutrophils, from the bone marrow into the during basal conditions monocytes, subsets of dendritic cells, and subsets of memory but also contributed to an impaired release of neutrophils in CD8+ T cells (21, 22). However, use of the anti-Ly6G mAb response to G-CSF, CXCL2, or L. monocytogenes infection (1A8) for neutrophil-specific depletion studies has shown that (37). This suggests that during L. monocytogenes infection, neutrophils are essential for clearance of L. monocytogenes,par- CXCR4 is essential for regulating neutrophil release from the ticularly from the liver (23, 24). Our studies have also estab- bone marrow. Under basal conditions, G-CSF may also play an lished that neutrophils are particularly important during high essential role in mobilization of neutrophils out of the bone by guest on September 28, 2021 L. monocytogenes inoculum, consistent with previous reports marrow, likely by decreasing concentrations of CXCL12 (39). indicating that after the administration of a high-dose infection, Neutrophil recruitment from the bone marrow may also be neutrophils ingest L. monocytogenes in the liver (20, 24). Another induced during infection or inflammation by host-derived recent report presented data that suggest neutrophils are not damage-associated molecular patterns, as well as pathogen- required for protection against L. monocytogenes. However, a associated molecular patterns (PAMPs) (40, 41). No current relatively low dose of infection was used and, importantly, studies illustrate L. monocytogenes–specific PAMPs that can neutrophils were depleted via i.p. injection of the 1A8 Ab at the induce neutrophil release or the role of CXCL1, CXCL2, or time of infection (25). It is possible that after i.v. infection and CXCL12 in the bone marrow during infection. However, one subsequent rapid arrival of L. monocytogenes at the target organs, could speculate that increased concentrations of G-CSF in- neutrophils were still present and contributed to early bacterial duced by L. monocytogenes infection would lead to decreased uptake and killing. Further highlighting the importance of concentrations of CXCL12 followed by a downregulation in neutrophils, mice lacking G-CSF, or its receptor, display severe neutrophil CXCR4 expression and enhanced release of neu- and are more susceptible to L. monocytogenes in- trophils from the bone marrow into circulation. fection than wild-type mice (26, 27). In addition, an increased Neutrophil extravasation into tissue. During L. monocytogenes presence of neutrophils in peripheral organs, resulting in in- infection, neutrophils that are released from the bone marrow creased resistance against L. monocytogenes, was observed in mice are subsequently recruited to infected organs, primarily the deficient in B7-H4, a molecule that inhibits growth of neu- liver. Efficient neutrophil is dependent on che- trophil progenitors (28). Another study showed that over- moattractant molecules that induce signaling pathways lead- activation of the innate , by high-dose ing to the rearrangement of intracellular structural molecules L. monocytogenes infection or preactivation with either heat- and upregulation of surface adhesion molecules. Formylated killed L. monocytogenes or synthetic TLR2-ligand followed by peptide receptors (FPRs) are highly expressed on neutrophils low-dose L. monocytogenes infection, led to significant neutrophil and can bind L. monocytogenes–derived formylated peptides apoptosis in the bone marrow and a subsequent increase in host (such as fMIVIL), resulting in a signaling cascade that induces susceptibility (29). neutrophil migration (42). Accordingly, mice deficient in Besides neutrophils, other phagocytic cells have well- FPR1, FPR2, or both are more susceptible to L. monocytogenes established roles during L. monocytogenes infection. Depletion infection and have delayed recruitment of neutrophils to the of splenic and liver macrophages during L. monocytogenes in- liver (42–44). This occurs in the absence of differences in fection results in increased mortality and bacterial burden (30, concentrations of common neutrophil-attracting chemokines, 31). Tissue macrophages are also involved in the production of suggesting that FPRs are responsible for initial chemotactic The Journal of Immunology 1559 signals to recruit neutrophils into the liver during L. monocytogenes Other cytokines that have been suggested to be important infection (43, 44). during L. monocytogenes infection, likely through indirect ef- The neutrophil-attracting chemokines CXCL1 and CXCL2 fects on neutrophils, include IL-1 and IL-6. IL-1a and IL-1b are produced in the liver post L. monocytogenes infection (38). are produced in the liver and spleen after L. monocytogenes Treatment with anti-CXCL2 (anti–MIP-2) Ab decreases infection, and exogenous IL-1a has been shown to increase neutrophil recruitment to the liver after L. monocytogenes neutrophil recruitment to sites of infection and decrease infection in wild-type mice, and Ab blockade of CXCR2 bacterial burden (56–59). Blocking the type 1 IL-1R, which completely ablated efficient neutrophil recruitment (38). binds both IL-1a and IL-1b, leads to increased susceptibility Conversely, mice deficient in the murine IL-8R homolog to L. monocytogenes (60). Interestingly, IL-1b–deficient mice (CXCR2) have previously been shown to be more resistant to show no difference in susceptibility to L. monocytogenes, sug- acute L. monocytogenes infection (45). However, this increased gesting a more central role for IL-1a (61). Studies performing resistance to infection is likely attributed to the extreme IL-1 depletion in SCID mice show increased susceptibility to observed in these mice (46, 47). Mice lacking the L. monocytogenes compared with untreated SCID mice, sug- type I IFNR show increased neutrophil recruitment to sites of gesting the mechanism of IL-1 protection is not mediated by infection and increased resistance to L. monocytogenes infec- T cells (62). However, further studies are required to deter- tion compared with wild-type mice. Pharmacological inhibi- mine how IL-1a mediates its protective effects, particularly in tion of CXCR2 in type I IFNR–deficient mice reversed both relation to neutrophils, during L. monocytogenes infection. the enhanced neutrophil recruitment and the increased re- Mice deficient for IL-6 are more susceptible to L. monocytogenes Downloaded from sistance to infection (48). Collectively, these data suggest that infection with increased bacterialburdeninbothspleenand FPRs are required for initial extravasation into the liver with liver and deficient neutrophil recruitment into the blood subsequent chemokine receptor signaling implicated in neu- compared with wild-type mice (63, 64). Addition of rIL-6 to trophil recruitment to the site of L. monocytogenes infection wild-type mice was able to provide enhanced protection against within the tissue. L. monocytogenes. Use of the anti–GR-1 Ab for depletion,

Mature neutrophils upregulate expression of adhesion mol- although not specific for neutrophils, eliminated the IL-6– http://www.jimmunol.org/ ecules resulting in efficient extravasation into tissues. Specific induced protective effect, suggesting IL-6 can directly or adhesion molecules expressed on neutrophils include LFA-1 indirectly enhance recruitment, and possibly function, of (CD11a/CD18) and Mac-1 (CD11b/CD18, CR3) (49). In- neutrophils (63). Interestingly, in IL-6 KO mice, no differences terestingly, CD18 knockout (KO) mice (deficient for LFA-1 were observed in NK cell or macrophage activation, and there and Mac-1) display increased resistance to L. monocytogenes was no difference in IFN-g production during L. monocytogenes infection, probably because of increased presence of neutrophils infection, further highlighting the potential link between IL-6 in the periphery caused by increased concentrations of G-CSF and neutrophils (63). Although it has been shown that classical

(50). Similarly, mice deficient in CD11a (LFA-1) are more IL-6 signaling, rather than IL-6 trans signaling, is required for by guest on September 28, 2021 resistant to L. monocytogenes infection, have increased infiltra- protection against L. monocytogenes, the cells responsible for tion of neutrophils into the liver, and have increased concen- producing and responding to IL-6 during infection are not trations of both G-CSF and IL-17. Furthermore, neutrophil known (65). depletion (using the GR-1 Ab) in LFA-1–deficient mice ab- Extracellular superoxide dismutase (SOD3; ecSOD) is the rogated the increased resistance to L. monocytogenes (51). responsible for regulating extracellular concentrations Conversely, Ab blockade of CD11b (Mac-1) results in a re- of ROS and protecting host tissues during inflammation. Our duction of neutrophil recruitment to the site of L. monocytogenes laboratory has shown that ecSOD activity results in increased infection in the liver and decreased resistance to L. monocytogenes neutrophil recruitment to the liver during L. monocytogenes infection (30, 52). Collectively, these data suggest that LFA-1 infection, possibly facilitated by the enzyme’s ability to expression restricts neutrophil recruitment to sites of infection protect the extracellular matrix from degradation leading leading to increased bacterial burden, whereas Mac-1, particu- to enhanced neutrophil trafficking. However, the increased larly the CD11b component, is essential for neutrophil re- number of neutrophils did not correlate with protection cruitment and control of L. monocytogenes infection. during infection, because mice with high ecSOD activity are Indirect regulation of neutrophil chemotaxis. During L. mono- more susceptible to L. monocytogenes than mice with wild-type cytogenes infection, IL-23 regulates the production of IL-17A ecSOD activity or mice deficient in ecSOD. Furthermore, in and IL-17F from gd T cells, resulting in optimal liver neutro- mice with high ecSOD activity, neutrophils did not effectively phil recruitment and enhanced bacterial clearance presumably colocalize with bacterial lesions in the liver, suggesting not because of increased chemokine production. Mice lacking IL- only chemotactic, but potentially functional defects (66). 23p19, IL-17A, or IL-17RA have increased bacterial burdens in Ultimately, rapid recruitment out of the bone marrow and the liver, which corresponds with decreased neutrophil recruitment efficient chemotaxis to sites of infection are essential preludes (53, 54). One study showed that increased concentrations of to neutrophil function and clearance of L. monocytogenes in- CCL8 (MCP-2) led to an influx of IL-17–producing gd Tcells fection. in mice conditionally knocked out for B –induced maturation protein-1 in macrophages. This resulted in a Neutrophil function during L. monocytogenes infection subsequent enhancement of neutrophil recruitment to sites of Neutrophil phagocytosis and containment of bacteria. Upon re- infection and increased clearance of L. monocytogenes (55). cruitment to foci of infection, particularly within the liver, These studies demonstrate the importance of chemokine neutrophils recognize and phagocytose L. monocytogenes.Spe- regulation in effective neutrophil recruitment and ultimately, cific receptors, including the complement receptor of the Ig clearance of bacteria. superfamily, have been shown to be required for macrophage 1560 BRIEF REVIEWS: NEUTROPHILS AND LISTERIA phagocytosis of L. monocytogenes (67); however, the receptors pretreatment of wild-type micewitha4-1BBagonistAbled and ligands that induce phagocytosis by neutrophils are currently to decreased bacteria burden and increased neutrophil ROS unknown. The majority of bacteria recovered from the liver production, suggesting a role for TNFRs in activation of immediately post high-dose i.v. infection with L. monocytogenes signaling pathways leading to production of ROS during are presumed to be extracellular and many are associated with L. monocytogenes infection (71). hepatocytes. However, the rapid influx of neutrophils to the liver Neutrophil activation during L. monocytogenes infection 2 during the first 6 h postinfection leads to a significant reduction induces production of O2· and H2O2, both of which are in the bacterial burden. In addition, depletion using the anti– and thought to be important for bacterial kill- GR-1 Ab preinfection, although not specific for neutrophils, led ing. The NADPH oxidase complex assembles on the phag- to markedly increased hepatocyte damage and increased osome in neutrophils and converts molecular oxygen (O2) 2 bacterial burden (20). Collectively, these data suggest that early into O2· (72). The NADPH oxidase complex is composed phagocytosis of L. monocytogenes by incoming neutrophils is of six subunits: gp91phox and p22phox are membrane-bound essential for protection of the liver against infection. components, whereas p47phox, p67phox, and p40phox are all Neutrophil phagocytosis of bacteria may not necessarily cytosolic components that assemble with the membrane- result in bacterial killing but may instead limit the spread of bound portion, and either Rac1 or Rac2 , upon ac- L. monocytogenes. The bacteria-filled neutrophils could then tivation of the cell (73). Mice that lack the essential gp91phox be phagocytosed by macrophages, ultimately killing the bacte- component of NADPH oxidase are more susceptible to ria. One study demonstrated the presence of L. monocytogenes L. monocytogenes during the early stages of infection (74–76). Downloaded from inside liver neutrophils that were located inside Kupffer cells Interestingly, mice deficient in the p47phox component have (30). Furthermore, the Mac-1 receptor on neutrophils can equivalent bacterial burden to wild-type mice during bind to ICAM-1 (CD54) on the surface of macrophages and L. monocytogenes infection (77). Lack of the p47phox subunit may potentially facilitate phagocytosis of infected neutrophils by be compensated for by high concentrations of the p67phox 2 Kupffer cells. It has been shown that inhibition of either subunit, leading to efficient O2· production; however, this has

CD11b (Mac-1) or ICAM-1 resulted in a reduced clearance not been thoroughly investigated in vivo (78). In addition to http://www.jimmunol.org/ of L. monocytogenes in the liver, although this could be related ROS production by the NADPH oxidase complex, it has to altered recruitment in addition to blockade of neutrophil– been shown that mitochondria-generated ROS is important macrophage interactions (30). Therefore, one could specu- for -mediated bacterial killing, although L. mono- late that the contribution of neutrophils to protection against cytogenes was not used in this study (79). Furthermore, efficient L. monocytogenes infection is purely related to bacterial localization with the mitochondria, mediated by containment. the Mst1 and Mst2 kinases, is required for optimal induction Neutrophils produce matrix metalloproteinase-8 (MMP8) of ROS downstream of TLR signaling, and mice lacking both

and store it in granules until bacterial sensing induces de- Mst1 and Mst2 show increased susceptibility to L. monocytogenes by guest on September 28, 2021 granulation at sites of phagocytosis allowing MMP8 to be compared with wild-type mice (80). taken into the phagosome with L. monocytogenes where it was Although ROS are potent bactericidal molecules, they can also shown to degrade LLO. It was further proposed that this leads causehosttissuedamageandmustthereforebeproperlyregu- to bacterial containment by preventing L. monocytogenes es- lated. The negative regulator of ROS (NRROS) is a recently cape from the phagosome. These in vitro studies showed that described protein important for preventing tissue damage to host inhibition of neutrophil led to increased cell organs by limiting phagocytic production of ROS. Increased damage, and inhibition of proteases led to decreased LLO ROS production, increased resistance to L. monocytogenes in- degradation and increased intracellular neutrophil bacterial fection, and increased tissue damage were all observed in mice 2 burden, supporting a potential role for MMP8 and other deficient in NRROS (81). The O2· generated by NADPH contents in protecting the host against L. monocytogenes oxidase is converted into H2O2 by SODs. In the extracellular 2 infection (68). milieu, ecSOD catalyzes the conversion of O2· to H2O2 to Neutrophil production of ROS. Direct sensing of L. monocytogenes protect the host from excessive tissue damage. Our laboratory by murine neutrophils is thought to be mediated primarily by has previously shown that during L. monocytogenes infection, formylated peptides binding to the receptor FPR1 on neu- mice with high ecSOD activity have increased bacterial burden trophils, which induces a signaling cascade leading to cal- and neutrophil apoptosis, as well as impaired neutrophil-specific 2 cium efflux and subsequent superoxide (O2· ) and hydrogen production of TNF-a, compared with ecSOD wild-type or peroxide (H2O2) production (42). Lack of FPR1 results ecSOD KO mice. Depletion of neutrophils in mice with high in increased bacterial burden and decreased production of ecSOD activity slightly decreases bacterial burden, whereas 2 O2· and H2O2 by neutrophils (43). Regulation of calcium neutrophil depletion in ecSOD wild-type or ecSOD KO mice entry is an important factor in neutrophil function, including results in increased bacterial burden, suggesting ecSOD activity 2 production of ROS, and is mediated by molecules such as leads to impaired neutrophil function (66). Although O2· and stromal-interacting molecule 1 (STIM1). Mice deficient in H2O2 are produced by activated neutrophils, hypochlorous STIM1 have decreased production of ROS and increased acid is believed to be a more potent bactericidal ROS molecule susceptibility to L. monocytogenes infection (69). Mice de- (82, 83). Production of is catalyzed by ficient for 4-1BB (CD137), a member of the TNFR super- in the presence of H2O2 and chloride ions. family constitutively expressed by neutrophils, are more Neutrophil-specific myeloperoxidase activity against L. mono- susceptible to L. monocytogenes infection than wild-type mice, cytogenes has not been determined, although it has been im- which correlates with defective calcium mobilization and plicated as being important for neutrophil antimicrobial decreased ROS production from neutrophils (70). Furthermore, activity against other bacterial pathogens (84). The Journal of Immunology 1561

In addition to ROS, neutrophils can generate RNS through L. monocytogenes, but neutrophil recruitment and function are the expression of iNOS (or NOS2), an enzyme that converts independent of MyD88 signaling. O2 to NO (NO). NOS2-deficient mice were found to be Whereas TLRs are responsible for recognizing a wide array more susceptible to L. monocytogenes infection than wild-type of extracellular or vesicular pathogens, Nod-like receptors mice (75, 85). Conversely, a more recent study showed that (NLRs) are positioned in the cytosol to recognize PAMPs pharmacologic inhibition of NOS2 resulted in decreased expressed by pathogens that escape the phagosome. Mice bacteria burden in the liver postinfection with L. mono- deficient in NOD1 have increased bacterial burden during cytogenes (86). Why different approaches to eliminating L. monocytogenes infection, which correlates with a decrease in NOS2 function resulted in different outcomes and, impor- neutrophil recruitment. However, it was determined that tantly, whether NOS2 is required for neutrophil killing in NOD1 signaling was essential in nonhematopoietic, but not vivo during L. monocytogenes infection still need to be re- hematopoietic, cells during infection (90). Furthermore, neu- 2 solved. Peroxynitrite (NO3· ), an ROS molecule produced trophils from RIP2 KO mice, which cannot signal through 2 by a reaction between O2· and NO, is also thought to have NOD1 or NOD2, did not display altered production of IL-6, very potent bactericidal activities, including the ability to kill TNF-a, CXCL1, or CXCL2 in response to L. monocytogenes L. monocytogenes in vitro (87). However, these activities have infection, as compared with neutrophils from wild-type mice not yet been identified as neutrophil specific, nor have they (91). This suggests that NLR signaling may be a redundant, been shown to be required for killing in vivo. rather than essential, pathway to induce neutrophil

Neutrophil production of cytokines. Neutrophil activation induced production during infection with L. monocytogenes. One Downloaded from by L. monocytogenes infection also results in the production of member of the NLR family, NLRP6, has been suggested to be several cytokines that have been deemed important for resis- a negative regulator of inflammatory responses during infec- tance to bacterial infection. Generally, recognition of micro- tion with L. monocytogenes. Mice deficient in NLRP6 show bial products by pattern recognition receptors initiates signaling increased survival and decreased bacterial burden post pathways through adaptor molecules leading to activation of L. monocytogenes infection. In addition, NLRP6-deficient the NF-kB transcription factor and, ultimately, production of mice exhibit increased IL-6 and CXCL1 concentrations in http://www.jimmunol.org/ cytokines. circulation and in the peritoneum correlating with increased + It has been shown that mice lacking MyD88 (a TLR adaptor recruitment of GR-1 cells to sites of infection (92). protein) are very susceptible to L. monocytogenes infection, A recent study identified the Sox2 transcription factor acting have reduced production of IL-6, IL-12, IL-18, IFN-g, and in the cytosol of neutrophils as a sensor of bacterial DNA. TNF-a, and decreased neutrophil recruitment to the spleen Upon recognition of bacterial DNA, such as that from (32, 88). Mice with MyD88 expression exclusive to dendritic L. monocytogenes, Sox2 initiates a signaling cascade ultimately cells responded comparably with wild-type mice during in- resulting in production of proinflammatory cytokines, in-

fection with L. monocytogenes (89). These data suggest that cluding TNF-a and IL-6. In addition, mice with phagocyte- by guest on September 28, 2021 MyD88 is required in dendritic cells for optimal responses to specific Sox2 deficiency exhibited increased susceptibility to

FIGURE 1. Neutrophil recruitment and function during L. monocytogenes infection. (A) Upon L. monocytogenes infection, neutrophils are rapidly released out of the bone marrow, where they travel through the circulation and into sites of infection, especially the liver. Direct interactions via chemokine/chemokine receptors, adhesion molecules, and FPRs, as well as indirect effects of cytokines/cytokine receptors, are involved. (B) Neutrophil function upon recognition of bacteria or bacterial products includes phagocytosis, killing via ROS/RNS, and production of proinflammatory cytokines. 1562 BRIEF REVIEWS: NEUTROPHILS AND LISTERIA

L. monocytogenes infection and because Sox2 is not expressed in spleen and liver and decreased host survival (104). Furthermore, macrophages, this indicates that Sox2 is a novel and essential depletion of neutrophils during L. monocytogenes infection de- sensor of L. monocytogenes in neutrophils (93). Mice deficient in creases the amount of TNF-a produced, correlating with in- Toso, an for IgM with previously unknown func- creased bacterial burden (24). Decreased neutrophil activation tion, predominantly displayed decreased production of TNF-a, because of deficiency of FPR1 or 4-1BB also resulted in a de- IL-6, and IL-12, as well as decreased phagocytic ability by crease in TNF-a production (42, 71). Although the precise role and a concurrent increase in bacterial burden post of TNF-a produced by neutrophils during L. monocytogenes L. monocytogenes infection (94). These recent studies highlight infection is not known, it is possible that hepatocytes are lysed novel bacterial sensors and signaling pathways in neutrophil by the actions of neutrophil-specific TNF-a production. A activation during L. monocytogenes infection. previous study has shown that neutrophil depletion with the Deficiency in IFN-g or the IFN-gR renders mice highly GR-1 Ab led to increased liver damage assessed by increased susceptible to infection with L. monocytogenes (32, 36, 95, 96). AST concentrations in serum (30). Additional studies using Multiple subsets of can produce IFN-g during microscopy have suggested that depletion of neutrophils with L. monocytogenes infection (97), and our studies have shown that the GR-1 Ab results in decreased hepatocyte death at 24 h Ag-independent responses of memory CD8+ T cells are supe- postinfection (16). Furthermore, TNF-a has been shown to rior to NK cells at providing protection when transferred directly induce hepatocyte lysis (105, 106). Initially, neutrophil into IFN-g–deficient hosts (98). Interestingly, one study phagocytosis of L. monocytogenes could limit hepatocyte infec- observed neutrophil-specific production of IFN-g during tion, and at later time points neutrophil TNF-a production Downloaded from L. monocytogenes infection and showed that transferring neu- could induce hepatocyte death, thus reducing the cell-to-cell trophils from wild-type mice into IFN-g KO mice increased spread of L. monocytogenes. bacterial clearance (99), suggesting that multiple cells have the capacity to provide IFN-g–mediated protection against Importance of neutrophils during secondary L. monocytogenes infection L. monocytogenes.MicedeficientinTNF-a,aproinflammatory Initial depletion studies using the anti–GR-1 Ab (RB6-8C5) cytokine produced by immune cells, or its receptor TNFR1, concluded that neutrophils are critically important for host http://www.jimmunol.org/ are highly susceptible to L. monocytogenes infection (100–103). defense during secondary L. monocytogenes infection (18, In addition, mice conditionally knocked out for phagocyte- 107). However, because it is known that anti–GR-1 depletes specific TNF-a display extreme susceptibility to L. monocytogenes multiple cell types in addition to neutrophils, interpretation infection characterized by increased bacterial burden in the of these data are challenging. Recent studies in our laboratory

Table I. Molecules implicated in neutrophil recruitment and function during L. monocytogenes infection

Effect on Resistance to by guest on September 28, 2021 Factor Effect on Neutrophil Recruitment Effect on Neutrophil Function L. monocytogenes References G-CSF (KO) General neutropenia Unknown Decreased 25, 26 G-CSFR (KO) General neutropenia Unknown Decreased 25, 26 B7-H4 (KO) Increased recruitment to No effect on ROS or Increased 27 sites of infection phagocytosis FPR1 and FPR2 (KO) Delayed recruitment to liver Decreased TNF-a and ROS Decreased 41–43 production IL-23p19 (KO) Deficient recruitment to liver Unknown Decreased 53 IL-17RA (KO) Deficient recruitment to liver Unknown Decreased 53 IL-17A (KO) Deficient recruitment to liver Unknown Decreased 52 BLIMP1 (KO) Increased recruitment Unknown Increased 54 IL-6 (KO) Decreased recruitment into Unknown Decreased 64, 65 circulation ecSOD (KO) Decreased recruitment to liver Enhanced TNF-a production Increased 67 CD11a (KO) Increased recruitment to liver Unknown Increased 50 CD11b (blocking) Reduced recruitment to liver Unknown Decreased 29, 51 CD18 (KO) General neutrophilia Unknown Increased 49 STIM1 (KO) No effect Decreased ROS production Decreased 70 gp91phox/NADPH Unknown Unknown Decreased 75–77 oxidase (KO) P47phox (KO) Unknown Unknown No effect 78 NRROS (KO) Unknown Unknown Increased 82 iNOS/NOS2 (KO) Unknown Unknown KO: decreased KO: 76, 86 (blocking) Blocking: increased Blocking: in liver; no effect in 87 spleen Sox2 (phagocyte-specific No effect on recruitment Defective bacterial sensing Decreased 94 KO; not expressed into blood; unknown effect on in macrophages) recruitment to sites of infection Toso (KO) Unknown Decreased phagocytosis and Decreased 95 impaired cytokine production 4-1BB/CD137 (KO) Unknown Decreased TNF-a and ROS Decreased 71 production TNF-a (phagocyte-specific KO) Unknown Defective TNF-a production Decreased 100 BLIMP1, B lymphocyte–induced maturation protein-1. 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