sign in sign up
<<
Home , Macrophage, Macrophage polarization

Polarization in Bacterial Infections Marie Benoit, Benoît Desnues and Jean-Louis Mege This information is current as J Immunol 2008; 181:3733-3739; ; of September 24, 2021. doi: 10.4049/jimmunol.181.6.3733 http://www.jimmunol.org/content/181/6/3733 Downloaded from References This article cites 68 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/181/6/3733.full#ref-list-1

Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision

• No Triage! Every submission reviewed by practicing scientists

• Fast Publication! 4 weeks from acceptance to publication

*average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts

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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. in Bacterial Infections Marie Benoit, Benoît Desnues, and Jean-Louis Mege1

Converging studies have shown that M1 and M2 mac- tokines and microbial products (2). More recently, M2 macro- rophages are functionally polarized in response to mi- phages have been characterized by functional expression of al- croorganisms and host mediators. Gene expression ternative activation markers. M2 include at least profiling of macrophages reveals that various Gram- three subsets: M2a, induced by IL-4 or IL-13; M2b, induced by negative and Gram-positive induce the tran- immune complexes and agonists of TLRs or IL-1 receptors; and scriptional activity of a “common host response,” M2c, induced by IL-10 and hormones (10). M1 which includes genes belonging to the M1 program. and M2 macrophages differ in terms of receptors, and expression, and effector functions (Fig. 1). Whereas However, excessive or prolonged M1 polarization can Downloaded from lead to tissue injury and contribute to pathogenesis. M1 macrophages are microbicidal and inflammatory (postin- The so-called M2 macrophages play a critical role in fectious pathogenesis), M2 macrophages are immunomodu- the resolution of by producing anti- lators (M2a and M2c) and are poorly microbicidal. Thus, inflammatory mediators. These M2 cells cover a contin- macrophageactivationcanbeeitherpro-inflammatoryoranti- uum of cells with different phenotypic and functional inflammatory. However, these extreme and simplified polar- properties. In addition, some bacterial induce ization states (M1 vs M2) actually describe a complex process http://www.jimmunol.org/ delineating a continuum of functional states. Recently, mac- specific M2 programs in macrophages. In this review, rophage activation has been shown to be plastic, rapid, and we discuss the relevance of macrophage polarization in fully reversible, suggesting that macrophage populations are three domains of infectious diseases: resistance to infec- dynamic and may first take part in inflammation and then tion, infectious pathogenesis, and chronic evolution of participate in its resolution (11). Consequently, macro- infectious diseases. The Journal of Immunology, 2008, phages display progressive functional changes resulting from 181: 3733–3739. changes in the microenvironment (12). In this review, we

will delineate the significance of macrophage polarization in by guest on September 24, 2021 ntigen-presenting cells such as /macro- the context of in acute and chronic infec- phages play major roles as sentinels for first line alerts tious diseases. A or as mediators that shape the adaptive immune re- sponse (1). Once activated by microbial products, macrophages Common macrophage responses to bacteria acquire microbicidal competence that usually leads to effective (2). However, several bacterial pathogens have Several studies suggest that host cells exposed to different evolved strategies to interfere with macrophage activation and groups of pathogens respond with common transcriptional ac- to modulate host responses (3). tivation programs, referred to as the core response to infection. Macrophages are dynamic and heterogeneous cells; this is A comparison of data collected from 32 published transcrip- due to different mechanisms governing their differentiation, tional-profiling studies show that a cluster of 511 genes, the tissue distribution, and responsiveness to stimuli (4, 5). The “common host response,” is coregulated in innate immune cells heterogeneity of undifferentiated circulating monocytes may in response to 77 pathogens, including bacteria, , and affect their polarization once they arrive in tissues (6, 7). In ad- fungi (13). In human peripheral leukocytes stimulated with dition, the microenvironment, such as intestines, adipose tis- Gram-negative and Gram-positive bacteria, some genes encod- sue, or alveolar space, may also constrain the functional prop- ing inflammatory and cell-to-cell signaling molecules are also erties of macrophages (8, 9). Polarized macrophages have been commonly regulated (14). Finally, Nau and colleagues have broadly classified into two groups: M1 and M2 macrophages. shown that human -derived macrophages respond During the 1970s, classically activated M1 macrophages were with a robust and shared pattern of gene expression to a broad described as responsive to two signals, type 1 inflammatory cy- range of bacteria (15).

Unite´de Recherche sur les Maladies Infectieuses Transmissibles et Emergentes, Centre 1 Address correspondence and reprint requests to Prof. Jean-Louis Mege, Unite´de Recher- National de la Recherche Scientifique-Institut de Recherche pour le De´veloppement, che sur les Maladies Infectieuses Transmissibles et Emergentes, Centre National de la Re- Unite´Mixte de Recherche 6236, Institut Fe´de´ratif de Recherche 48, Universite´delaMe´di- cherche Scientifique-Institut de Recherche pour le De´veloppement, Unite´Mixte de Re- terrane´e, Faculte´deMe´decine, Marseille, France cherche 6236, Faculte´deMe´decine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France. E-mail address: [email protected] Received for publication May 13, 2008. Accepted for publication July 21, 2008. The costs of publication of this article were defrayed in part by the payment of page charges. Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. www.jimmunol.org 3734 BRIEF REVIEWS: MACROPHAGE POLARIZATION IN BACTERIAL INFECTIONS

cules such as CD80 and CD86. IL-1ra appears to be the only gene associated with M2 polarization that is expressed after bac- terial challenge. It is likely that this robust M1-shifted activa- tion corresponds to the common alarm signal against bacteria induced in macrophages, as most of these genes are induced in- dependently of the bacterial species.

M1 polarization and control of acute infectious diseases The M1 program of macrophages is usually associated with pro- tection during acute infectious diseases. For instance, monocytogenes, which causes disease in immunocompromised patients and pregnant women, induces an M1 program, thus preventing bacterial escape and stimulating intra- cellular killing of bacteria in vitro and in vivo (25). Mice lacking IFN-␥ and TNF, two canonical markers of M1 polarization, and their respective receptors die from L. monocytogenes infec- tion (26). Similarly, typhi, the agent of typhoid ,

and Salmonella typhimurium, a gastroenteritis agent, induce the Downloaded from M1 polarization of human and murine macrophages, and this induction is associated with the control of the infection. FIGURE 1. General concepts and properties of polarized macrophages. The protective role of M1 macrophages has been exemplified Classically activated macrophages (M1) are induced through LPS and/or mi- crobial product stimulation. Their inflammatory repertoire is characterized by in mice deficient for components of the IL-12 pathway (27). the secretion of proinflammatory mediators and the release of reactive The initial transcriptomic analysis of mouse macrophage re- and nitrogen intermediates (ROI and RNI, respectively). In contrast, alter- sponses to reveals an overlap of http://www.jimmunol.org/ native activation of macrophages (M2) covers a continuum of functional genes modulated by mycobacteria and IFN-␥, which corre- states classified as M2a, induced by IL-4/IL-13, M2b, induced by immune sponds to an M1 program (28). In addition, during the early complexes and TLR agonists, and M2c, induced by IL-10 and glucocorti- phase of M. tuberculosis infection, macrophages are polarized coid hormones. toward an M1 profile (29), which is in agreement with clinical data collected from patients with active tuberculosis. However, a small subset of tuberculosis patients is characterized by M2- Although these studies reveal a core reprogramming of the type patterns, which can be reversed by treatment host transcriptome during infection, none focuses on macro-

(30). Other mycobacterial diseases such as Buruli disease (My- by guest on September 24, 2021 phage polarization as a result of host- interactions. In cobacterium ulcerans) and opportunistic infections (Mycobacte- this review, we collate and compare microarray data from 12 rium avium) are also characterized and controlled by M1 polar- studies released into public databases (14–24) and from unpub- ization of macrophages (31, 32). lished results (Gene Expression Omnibus record number: Similarly, the acute phase of chlamydial infections is char- GSE5765). These studies represent transcriptional responses of acterized by protective M1 polarization as emphasized in mononuclear to diverse bacteria and bacterial com- Ϫ Ϫ Ϫ Ϫ IFN-␥ / IFN-␥R / mice or in mice treated with anti- ponents. The data sets were processed by considering modu- IFN-␥ Abs (33). NO is another feature of M1 polarization lated genes involved in M1/M2 polarization. Together, 87 known to be important in Salmonella infections (34); how- unique genes were extracted from these data and classified into ever, a role for NO has not been confirmed in murine models four families: cytokine/cytokine receptors, chemokine/chemo- of chlamydial infections. kine receptors, effector molecules, and pattern recognition re- ceptor/costimulation molecules. To avoid comparison biases Uncontrolled M1 polarization and infectious pathogenesis resulting from independent experiments performed on differ- ent platforms, we used a clustering analysis to permit the group- As mentioned above, M1 polarization supports resistance to in- ing of genes with a common expression pattern across samples. tracellular bacteria and controls the acute phase of infection. The resulting matrix displays color-coded gene expression ra- However, an excessive or prolonged M1 program is deleterious tios, where green represents down-regulated gene transcription for the host, as demonstrated in acute infections with Esche- and red represents up-regulated gene transcription. richia coli or Streptococcus sp. E. coli causes many diseases, in- The common response of macrophages to bacterial infections cluding gastroenteritis, urinary tract infections, neonatal men- mainly involves the up-regulation of genes involved in M1 po- ingitis, and . Sepsis couples systemic inflammatory larization (Fig. 2). These include genes encoding such response with , leading to tissue damage as TNF, IL-6, IL-12, IL-1␤, cytokine receptors such as IL-7R and multiple organ failure (35). In vitro, E. coli induces a typical and IL-15RA, such as CCL2, CCL5, and CXCL8, M1 profile through the recognition of LPS by TLR4 (36, 37). Signaling mechanisms include NF-␬B activation, LPS-induced and the chemokine receptor CCR7. Other M1-associated up- ␣ regulated genes encode the indoleamine-pyrrole 2,3 TNF- factor up-regulation (38), and PI3K pathway stimula- dioxygenase and NO synthase 2 (NOS2),2 which are involved tion (37). It has been demonstrated that M1 program induction in macrophage microbicidal activity, and costimulatory mole- and sepsis severity are related. In baboon experimental perito- nitis caused by E. coli, the M1 phenotype is prominent in ba- boons that die from the infection; in contrast, surviving ba- 2 Abbreviations used in this paper: NOS2, NO synthase 2; LIR, leukocyte Ig-like receptor. boons display a mixed M1/M2 activation phenotype (39). In The Journal of Immunology 3735 Downloaded from

FIGURE 2. Common transcriptional signature of macrophages in response to bacterial infections. Tran- http://www.jimmunol.org/ scriptional data from 12 studies on the response of human and mouse macrophages to several bacteria and bacterial components were analyzed by hierarchical clustering anal- ysis and represented by a color gradient from green (down- regulation) to red (up-regulation). Only genes involved in M1/M2 polarization that were modulated in at least one condition were included. Gray box represents unavailable data. Abbreviations/designations not defined elsewhere:

BCG. Bacillus Calmette-Gue´rin; BCGhsp65, BCG heat by guest on September 24, 2021 shock protein 65; B. melitensis, Brucella melitensis; B. per- tussis, Bordetella pertussis; C. pneumoniae, Chlamydophila pneumoniae; EHEC, enterohemorrhagic E. coli; L. pneu- mophila, ; LPS E, E. coli LPS; LPS S, Salmonella LPS; LTA, lipoteichoic acid; MDP, mu- ramyl dipeptide; M. leprae, Mycobacterium leprae; MPA, mycophenolic acid; S. aureus, Staphylococcus aureus; TBhsp70, tuberculosis heat shock protein 70. 3736 BRIEF REVIEWS: MACROPHAGE POLARIZATION IN BACTERIAL INFECTIONS patients with severe sepsis, high circulating concentrations of M1-type cytokines are highly correlated with mortality (40). Macrophages from these patients produce high levels of type 1 cytokines and chemokines that activate the and contribute to cardiac failure, loss of general organ perfusion, and death (41). Streptococcus species can cause meningitis, , endo- carditis, erysipelas, and necrotizing fasciitis in humans and other animals. Host responses are generally characterized by an intense inflammatory reaction and an M1 polarization of mac- rophages involving the TLR2-dependent pathway (42). Hu- man and murine macrophages differ in their responses to Strep- tococcus pyogenes. In humans, this pathogen induces a M1 profile characterized by enhanced mRNA expression of CCL2, CCL5, CXCL8, and CXCL10 (43). In mice S. pyogenes stimu- lates an unusual activation program that combines M1 and M2 profiles (44). In a murine model of pneumonia caused by S. pneumoniae, mortality correlates with inflammation and Downloaded from the presence of M1-polarized macrophages (45).

Bacteria-mediated interference with M1 polarization It is well established that intracellular bacteria subvert microbi- cidal effectors to survive in the hostile environment produced by macrophages. A growing number of studies show that some http://www.jimmunol.org/ pathogens have evolved different strategies to interfere with M1 polarization. Some Salmonella or Mycobacterium species neu- tralize M1-related effectors. S. typhimurium SPI-2 encodes me- diators that inhibit phagosome relocalization of NADPH oxi- dase, thus inhibiting the oxidative microbicidal activity of macrophages (46). Similarly, Mycobacterium bovis bacillus Calmette-Gue´rin interferes with NOS2 recruitment to phago- somes, inhibiting NO release (47). Other bacterial strategies in- by guest on September 24, 2021 clude inhibition of M1 cytokine expression/secretion. Salmo- nella dublin suppresses IL-18 and IL-12p70 production (48). FIGURE 3. Macrophage polarization and C. burnetii. C. burnetii stimulates Through the membrane protein Omp25, inhibits an M1 profile in monocytes that control bacterial replication. C. burnetii in- the production of TNF in human macrophages, leading to re- duces an atypical M2 profile in macrophages. M2 macrophages are unable to control C. burnetii replication, as observed during acute Q fever. In the presence duced production of IL-12 (49). Mycobacteria interfere with of M2 cytokines such as IL-10 or following the ingestion of apoptotic cells, C. M1 polarization through the secretion of virulence factors. burnetii-infected monocytes and macrophages are polarized toward M2 cells, Early secreted antigenic target protein-6 (ESAT-6) from M. tu- thus allowing for intense bacterial replication. This may be observed during the berculosis directly inhibits the activation of NF-␬B and IFN- chronic evolution of Q fever. regulatory factors downstream of TLR2 via Akt-dependent mechanisms (50). Mycobacteria also interfere with M1 activa- tion via indirect mechanisms. Macrophages are unable to kill and they fail to produce NO (24). As in mycobacterial infec- highly pathogenic strains of M. tuberculosis despite IFN-␥ stim- tions, it is likely that IL-6 interferes with the IFN-␥ pathway ulation; this is thought to rely on the transcriptional inhibition and contributes to chronic evolution of Q fever. Other patho- of IFN-␥-targeted genes through a bystander effect involving gens stimulate a clear-cut M2 program in macrophages. For in- IL-6 (51). Although IL-6 is classically associated with M1 po- stance, Yersinia enterocolitica infection of susceptible BALB/c larization, it can inhibit the production of a subset of IFN-␥- mice results in arginase-1 activation and TGF␤1 and IL-4 pro- responsive genes, including CXCL10 (52). duction (54). The M2 reprogramming of macrophages depends Coxiella burnetii is an obligate intracellular bacterium that on yersinial virulence factors; the infection of murine macro- causes Q fever, an acute disease with a risk of chronic evolution phages with bacteria defective for the Yop-encoded type III se- in immunocompromised patients, pregnant women, or patients cretion system results in M1 polarization (55). LcrV, another with valve disease (53). It elicits an M1 program in monocytes Yersinia sp. virulence factor, stimulates M2 polarization, prob- (our unpublished data) and an atypical M2 profile in macro- ably via the induction of IL-10 (56). phages combining M1/M2 characteristics (24). C. burnetii-in- fected macrophages release the M2-associated molecules IL-10, TGF␤1, and CCL18 and express and the ac- M2 polarization and chronic infectious diseases tive form of arginase-1. They also secrete high levels of IL-6 and Chronic evolution of infectious diseases is thought to be asso- CXCL8, two molecules associated with M1 polarization (Fig. ciated with macrophage reprogramming toward an M2 profile. 3). However, C. burnetii-infected macrophages do not express Chronic is associated with IL-10-mediated M2 po- other M1 molecules such as TNF, IL-12, CD80, and CCR7, larization. Neutralization of the M2-promoting cytokines The Journal of Immunology 3737

FIGURE 4. Whipple’s disease is associated with an M2 macrophage profile. In vitro, T. whipplei stimulates oppo- site polarization of monocytes and macrophages. T. whip- plei is killed by monocytes that are M1 polarized. In con- trast, T. whipplei replicates in macrophages that are M2 polarized. In patients with Whipple’s disease, T. whipplei is mainly detected in intestinal infiltrated macrophages. These macrophages are M2 polarized. This polarization may be due to the shift of leukocyte secretion from IL-2 and IFN-␥ toward IL-4 in response to Ag stimulation and to increased circulating levels of IL-16 and apoptotic cells.

IL-10 and IL-4 in susceptible mice allows Brucella abortus kill- of Q fever. Interestingly, IFN-␥ prevents C. burnetii replication ing by macrophages through IFN-␥ production and the resto- induced by apoptotic cells and reprograms monocytes and mac- ration of M1 profiles (57). The presence of M2 macrophages is rophages toward an M1 profile (67). This study clearly demon- Downloaded from also critical for the chronic fate of mycobacterial infections, and strates that M2 macrophages are associated with the chronic high levels of M2 macrophage-derived IL-10 are found in early evolution of Q fever only when type 1 mediators are absent. ulcerative lesions of Buruli disease (31). Similarly, in leproma- Whipple’s disease is a rare systemic disease caused by Troph- tous lesions, macrophages overexpress IL-10 (58) and members eryma whipplei; the chronic evolution of this disease is asso- of the leukocyte Ig-like receptor (LIR) family, including LIR-7. ciated with tissue infiltrates of foamy macrophages with M2 LIR-7 has been shown to suppress innate host defense mecha- profile characteristics (Fig. 4). In vitro, monocytes and mac- http://www.jimmunol.org/ nisms by shifting monocyte polarization toward an M2 profile rophages display different susceptibilities toward T. whipplei. associated with IL-10 secretion (59). LILRA2, another member Whereas the bacteria are killed by monocytes in which a mild of LIR family, is expressed in lepromatous lesions and enables M1 polarization is found, T. whipplei actively replicates in mac- the expression of specific cytokine pattern associating inflam- rophages in which an M2 profile is observed (17). Transcrip- matory cytokines and IL-10 in monocytes (60). - tional analysis has identified new candidates involved in mono- ϩ specific ICAM-grabbing nonintegrin-positive (DC-SIGN ) cyte and macrophage polarization. In T. whipplei-infected macrophages have been found in lepromatous lesions (61). macrophages, genes encoding CCL15 and IL-16 are up-regu-

Their differentiation requires TLR and IL-15, known to en- lated. Interestingly, IL-16 promotes T. whipplei replication in by guest on September 24, 2021 hance the microbicidal competence of macrophages (62). Al- monocytes and enhances bacterial growth in macrophages, sug- though lepromatous is considered a paradigm of Th2 gesting that IL-16 might play a role in M2 polarization. The response, the status of macrophages in patients is not consistent transcriptional profile of intestinal infiltrating cells, mainly with a M2 profile. comprised of macrophages, has been investigated in a biopsy The pivotal role of IL-10 in chronic Q fever and the replica- from a patient with intestinal Whipple’s disease (68). CCL18, tion of C. burnetii within macrophages has been demonstrated Scavenger receptor, CD14, IL-1ra, and IL-10 are markedly up- in vitro and in vivo (Fig. 3). IL-10 is overproduced by mono- regulated in the infected intestinal tissue, consistent with an M2 cytes from patients with Q fever endocarditis, the major clinical profile of infiltrated macrophages. Notably, M2 polarization in expression of the chronic disease (63), and is sufficient to drive intestinal tissue is almost identical to that observed in macro- bacterial replication via altered phagosome biogenesis (64). In phages treated in vitro with IL-4 and IL-13. transgenic mice overexpressing IL-10 in macrophages, the tis- sue burden of C. burnetii increases while formation is impaired. These macrophages are characterized by the up- Conclusions regulation of arginase-1, Yim 1/2, and mannose receptor and by Analysis of gene expression has revealed a continuum of activa- the repression of NOS2 and inflammatory cytokines (65). The tion signatures in macrophages. From public databases, it is M2 profile of macrophages has also been observed in a model of possible to summarize a “common host response” of macro- persistent infection in mice deficient for Vanin-1, a membrane- phages to bacterial infections with an M1 signature. Usually, anchored pantetheinase that controls tissue inflammation (66). the M1 signature is associated with the control of acute infec- In addition, the uptake of apoptotic cells by monocytes and tions, but it may also be responsible for infectious pathogenesis macrophages is critical for chronic evolution of Q fever (67). if uncontrolled. Some bacterial pathogens have evolved sophis- Patients with cardiac valve lesions who have elevated levels of ticated strategies to prevent M1 polarization, neutralize micro- circulating apoptotic leukocytes have the highest risk of devel- bicidal effectors of macrophage, or promote M2 polarization. oping endocarditis after acute Q fever. In monocytes, the inges- The persistence of bacterial pathogens in tissues and the chronic tion of apoptotic cells induces a program characterized by the evolution of infectious diseases are linked to macrophage repro- up-regulation of IL-10, IL-19, IL-20, IL-24 (three members of gramming toward heterogeneous M2 signatures. The develop- IL-10 family), IL-1ra, CCL18, and CCL24; in macrophages, ment of gene expression analysis in clinical situations will be expression of CD14, TGF␤1, IL-1ra, IL-10, CCL16, and man- essential to understand the precise role of macrophage polariza- nose receptor is markedly increased. This pattern is associated tion in resistance/susceptibility to infection, clinical expression, with C. burnetii replication and accounts for chronic evolution and prognosis of infectious diseases. 3738 BRIEF REVIEWS: MACROPHAGE POLARIZATION IN BACTERIAL INFECTIONS

30. Raju, B., Y. Hoshino, I. Belitskaya-Levy, R. Dawson, S. Ress, J. A. Gold, R. Condos, Disclosures R. Pine, S. Brown, A. Nolan, et al. 2008. Gene expression profiles of bronchoalveolar The authors have no financial conflict of interest. cells in pulmonary TB. Tuberculosis (Edinb.) 88: 39–51. 31. Kiszewski, A. E., E. Becerril, L. D. Aguilar, I. T. Kader, W. Myers, F. Portaels, and R. Hernandez Pando. 2006. The local in ulcerative lesions of Buruli References disease. Clin. Exp. Immunol. 143: 445–451. 1. Hoebe, K., E. Janssen, and B. Beutler. 2004. The interface between innate and adap- 32. Murphy, J. T., S. Sommer, E. A. Kabara, N. Verman, M. A. Kuelbs, P. Saama, tive immunity. Nat. Immunol. 5: 971–974. R. Halgren, and P. M. Coussens. 2006. Gene expression profiling of monocyte-de- 2. Mackaness, G. B. 1964. The immunological basis of acquired cellular resistance. rived macrophages following infection with Mycobacterium avium subspecies avium J. Exp. Med. 120: 105–120. and Mycobacterium avium subspecies . Physiol. Genomics 28: 67–75. 3. Russell, D. G. 2007. Who puts the tubercle in tuberculosis? Nat. Rev. Microbiol. 5: 33. Rottenberg, M. E., A. Gigliotti-Rothfuchs, and H. Wigzell. 2002. The role of IFN-␥ 39–47. in the outcome of chlamydial infection. Curr. Opin. Immunol. 14: 444–451. 4. Gordon, S. 2003. Alternative activation of macrophages. Nat. Rev. Immunol. 3: 34. Igietseme, J. U., L. L. Perry, G. A. Ananaba, I. M. Uriri, O. O. Ojior, S. N. Kumar, 23–35. and H. D. Caldwell. 1998. Chlamydial infection in inducible synthase 5. Mosser, D. M. 2003. The many faces of macrophage activation. J. Leukocyte Biol. 73: knockout mice. Infect. Immun. 66: 1282–1286. 209–212. 35. O’Reilly, M., D. E. Newcomb, and D. Remick. 1999. Endotoxin, sepsis, and the 6. Gordon, S., and P. R. Taylor. 2005. Monocyte and macrophage heterogeneity. Nat. primrose path. Shock 12: 411–420. Rev. Immunol. 5: 953–964. 36. Liang, M. D., A. Bagchi, H. S. Warren, M. M. Tehan, J. A. Trigilio, 7. Strauss-Ayali, D., S. M. Conrad, and D. M. Mosser. 2007. Monocyte subpopulations L. K. Beasley-Topliffe, B. L. Tesini, J. C. Lazzaroni, M. J. Fenton, and J. Hellman. and their differentiation patterns during infection. J. Leukocyte Biol. 82: 244–252. 2005. Bacterial peptidoglycan-associated lipoprotein: a naturally occurring Toll-like 8. Lambrecht, B. N. 2006. in the driver’s seat. Immunity 24: receptor 2 agonist that is shed into serum and has synergy with . 366–368. J. Infect. Dis. 191: 939–948. 9. Lumeng, C. N., J. L. Bodzin, and A. R. Saltiel. 2007. induces a phenotypic 37. Pinheiro da Silva, F., M. Aloulou, D. Skurnik, M. Benhamou, A. Andremont, switch in macrophage polarization. J. Clin. Invest. 117: 175–184. I. T. Velasco, M. Chiamolera, J. S. Verbeek, P. Launay, and R. C. Monteiro. 2007. 10. Mantovani, A., A. Sica, S. Sozzani, P. Allavena, A. Vecchi, and M. Locati. 2004. The CD16 promotes sepsis through an FcR␥ inhibitory pathway that pre- Downloaded from chemokine system in diverse forms of macrophage activation and polarization. Trends vents and facilitates inflammation. Nat. Med. 13: 1368–1374. Immunol. 25: 677–686. 38. Tang, X., D. Metzger, S. Leeman, and S. Amar. 2006. LPS-induced TNF-␣ factor 11. Porcheray, F., S. Viaud, A. C. Rimaniol, C. Leone, B. Samah, N. Dereuddre-Bosquet, (LITAF)-deficient mice express reduced LPS-induced cytokine: evidence for LITAF- D. Dormont, and G. Gras. 2005. Macrophage activation switching: an asset for the dependent LPS signaling pathways. Proc. Natl. Acad. Sci. USA 103: 13777–13782. resolution of inflammation. Clin. Exp. Immunol. 142: 481–489. 12. Stout, R. D., and J. Suttles. 2004. Functional plasticity of macrophages: reversible 39. Mehta, A., R. Brewington, M. Chatterji, M. Zoubine, G. T. Kinasewitz, G. T. Peer, adaptation to changing microenvironments. J. Leukocyte Biol. 76: 509–513. A. C. Chang, F. B. Taylor, Jr., and A. Shnyra. 2004. Infection-induced modulation of 13. Jenner, R. G., and R. A. Young. 2005. Insights into host responses against pathogens M1 and M2 phenotypes in circulating monocytes: role in immune monitoring and from transcriptional profiling. Nat. Rev. Microbiol. 3: 281–294. early prognosis of sepsis. Shock 22:.423–430. http://www.jimmunol.org/ 14. Boldrick, J. C., A. A. Alizadeh, M. Diehn, S. Dudoit, C. L. Liu, C. E. Belcher, 40. Bozza, F. A., J. I. Salluh, A. M. Japiassu, M. Soares, E. F. Assis, R. N. Gomes, D. Botstein, L. M. Staudt, P. O. Brown, and D. A. Relman. 2002. Stereotyped and M. T. Bozza, H. C. Castro-Faria-Neto, and P. T. Bozza. 2007. Cytokine profiles as specific gene expression programs in human innate immune responses to bacteria. markers of disease severity in sepsis: a multiplex analysis. Crit. Care 11: R49. Proc. Natl. Acad. Sci. USA 99: 972–977. 41. Lopez-Bojorquez, L. N., A. Z. Dehesa, and G. Reyes-Teran. 2004. Molecular mech- 15. Nau, G. J., J. F. Richmond, A. Schlesinger, E. G. Jennings, E. S. Lander, and anisms involved in the pathogenesis of . Arch. Med. Res. 35: 465–479. R. A. Young. 2002. Human macrophage activation programs induced by bacterial 42. Kadioglu, A., and P. W. Andrew. 2004. The innate immune response to pneumococ- pathogens. Proc. Natl. Acad. Sci. USA 99: 1503–1508. cal lung infection: the untold story. Trends Immunol. 25: 143–149. 16. Detweiler, C. S., D. B. Cunanan, and S. Falkow. 2001. Host microarray analysis re- 43. Veckman, V., M. Miettinen, S. Matikainen, R. Lande, E. Giacomini, E. M. Coccia, veals a role for the Salmonella response regulator phoP in human macrophage cell and I. Julkunen. 2003. Lactobacilli and streptococci induce inflammatory chemokine death. Proc. Natl. Acad. Sci. USA 98: 5850–5855. production in human macrophages that stimulates Th1 cell . J. Leukocyte 17. Desnues, B., D. Raoult, and J. L. Mege. 2005. IL-16 is critical for Tropheryma whipplei Biol. 74: 395–402. replication in Whipple’s disease. J. Immunol. 175: 4575–4582. 44. Goldmann, O., M. von Kockritz-Blickwede, C. Holtje, G. S. Chhatwal, R. Geffers, by guest on September 24, 2021 18. He, Y., S. Reichow, S. Ramamoorthy, X. Ding, R. Lathigra, J. C. Craig, B. W. Sobral, and E. Medina. 2007. Transcriptome analysis of murine macrophages in response to G. G. Schurig, N. Sriranganathan, and S. M. Boyle. 2006. Brucella melitensis triggers infection with Streptococcus pyogenes reveals an unusual activation program. Infect. Im- time-dependent modulation of and down-regulation of mitochondrion-as- mun. 75: 4148–4157. sociated gene expression in mouse macrophages. Infect. Immun. 74: 5035–5046. 45. Smith, M. W., J. E. Schmidt, J. E. Rehg, C. J. Orihuela, and J. A. McCullers. 2007. 19. Khajoee, V., M. Saito, H. Takada, A. Nomura, K. Kusuhara, S. I. Yoshida, Induction of pro- and anti-inflammatory molecules in a mouse model of pneumococ- Y. Yoshikai, and T. Hara. 2006. Novel roles of and CXC chemokine cal pneumonia after . Comp. Med. 57: 82–89. ligand 7 in the defence against mycobacterial infection. Clin. Exp. Immunol. 143: 46. Vazquez-Torres, A., Y. Xu, J. Jones-Carson, D. W. Holden, S. M. Lucia, 260–268. M. C. Dinauer, P. Mastroeni, and F. C. Fang. 2000. Salmonella pathogenicity island 20. Losick, V. P., and R. R. Isberg. 2006. NF-␬B translocation prevents host cell death 2-dependent evasion of the NADPH oxidase. Science 287: 1655–1658. after low-dose challenge by Legionella pneumophila. J. Exp. Med. 203: 2177–2189. 47. Miller, B. H., R. A. Fratti, J. F. Poschet, G. S. Timmins, S. S. Master, M. Burgos, 21. van Erp, K., K. Dach, I. Koch, J. Heesemann, and R. Hoffmann. 2006. Role of strain M. A. Marletta, and V. Deretic. 2004. Mycobacteria inhibit re- differences on host resistance and the transcriptional response of macrophages to in- cruitment to during macrophage infection. Infect. Immun. 72: fection with Yersinia enterocolitica. Physiol. Genomics 25: 75–84. 2872–2878. 22. Auffray, C., D. Fogg, M. Garfa, G. Elain, O. Join-Lambert, S. Kayal, S. Sarnacki, 48. Bost, K. L., and J. D. Clements. 1997. Intracellular Salmonella dublin induces sub- A. Cumano, G. Lauvau, and F. Geissmann. 2007. Monitoring of vessels and stantial secretion of the 40-kilodalton subunit of -12 (IL-12) but minimal tissues by a population of monocytes with patrolling behavior. Science 317: 666–670. secretion of IL-12 as a 70-kilodalton protein in murine macrophages. Infect. Immun. 23. Rodriguez, N., J. Mages, H. Dietrich, N. Wantia, H. Wagner, R. Lang, and 65: 3186–3192. T. Miethke. 2007. MyD88-dependent changes in the pulmonary transcriptome after 49. Dornand, J., A. Gross, V. Lafont, J. Liautard, J. Oliaro, and J. P. Liautard. 2002. The infection with Physiol. Genomics 30: 134–145. innate immune response against Brucella in humans. Vet. Microbiol. 90: 383–394. 24. Benoit, M., B. Barbarat, A. Bernard, D. Olive, and J. L. Mege. 2008. Coxiella burnetii, 50. Pathak, S. K., S. Basu, K. K. Basu, A. Banerjee, S. Pathak, A. Bhattacharyya, the agent of Q fever, stimulates an atypical M2 activation program in human macro- T. Kaisho, M. Kundu, and J. Basu. 2007. Direct extracellular interaction between the phages. Eur. J. Immunol. 38: 1065–1070. early secreted ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR 25. Shaughnessy, L. M., and J. A. Swanson. 2007. The role of the activated macrophage in signaling in macrophages. Nat. Immunol. 8: 610–618. clearing infection. Front Biosci. 12: 2683–2692. 51. Ting, L. M., A. C. Kim, A. Cattamanchi, and J. D. Ernst. 1999. Mycobacterium tu- 26. Pfeffer, K., T. Matsuyama, T. M. Kundig, A. Wakeham, K. Kishihara, A. Shahinian, berculosis inhibits IFN-␥ transcriptional responses without inhibiting activation of K. Wiegmann, P. S. Ohashi, M. Kronke, and T. W. Mak. 1993. Mice deficient for the STAT1. J. Immunol. 163: 3898–3906. 55 kd tumor factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73: 457–467. 52. Nagabhushanam, V., A. Solache, L. M. Ting, C. J. Escaron, J. Y. Zhang, and J. D. Ernst. 2003. Innate inhibition of adaptive immunity: Mycobacterium tuberculo- 27. Jouanguy, E., R. Doffinger, S. Dupuis, A. Pallier, F. Altare, and J. L. Casanova. 1999. ␥ IL-12 and IFN-␥ in host defense against mycobacteria and salmonella in mice and sis-induced IL-6 inhibits macrophage responses to IFN- . J. Immunol. 171: men. Curr. Opin. Immunol. 11: 346–351. 4750–4757. 28. Ehrt, S., D. Schnappinger, S. Bekiranov, J. Drenkow, S. Shi, T. R. Gingeras, 53. Raoult, D., T. Marrie, and J. L. Mege. 2005. Natural history and pathophysiology of T. Gaasterland, G. Schoolnik, and C. Nathan. 2001. Reprogramming of the macro- Q fever. Lancet Infect. Dis. 5: 219–226. phage transcriptome in response to -␥ and Mycobacterium tuberculosis: sig- 54. Tumitan, A. R., L. G. Monnazzi, F. R. Ghiraldi, E. M. Cilli, and naling roles of nitric oxide synthase-2 and phagocyte oxidase. J. Exp. Med. 194: B. M. Machado de Medeiros. 2007. Pattern of macrophage activation in Yersinia- 1123–1140. resistant and Yersinia-susceptible strains of mice. Microbiol. Immunol. 51: 1021–1028. 29. Chacon-Salinas, R., J. Serafin-Lopez, R. Ramos-Payan, P. Mendez-Aragon, 55. Hoffmann, R., K. van Erp, K. Trulzsch, and J. Heesemann. 2004. Transcriptional R. Hernandez-Pando, D. Van Soolingen, L. Flores-Romo, S. Estrada-Parra, and responses of murine macrophages to infection with Yersinia enterocolitica. Cell Micro- I. Estrada-Garcia. 2005. Differential pattern of cytokine expression by macrophages biol. 6: 377–390. infected in vitro with different Mycobacterium tuberculosis genotypes. Clin. Exp. Im- 56. Brubaker, R. R. 2003. Interleukin-10 and inhibition of innate immunity to Yersiniae: munol. 140: 443–449. roles of Yops and LcrV (V antigen). Infect. Immun. 71: 3673–3681. The Journal of Immunology 3739

57. Fernandes, D. M., X. Jiang, J. H. Jung, and C. L. Baldwin. 1996. Comparison of T 63. Capo, C., Y. Zaffran, F. Zugun, P. Houpikian, D. Raoult, and J. L. Mege. 1996. cell cytokines in resistant and susceptible mice infected with virulent Brucella abortus Production of interleukin-10 and transforming ␤ by peripheral blood strain 2308. FEMS Immunol. Med. Microbiol. 16: 193–203. mononuclear cells in Q fever endocarditis. Infect. Immun. 64: 4143–4147. 58. Sieling, P. A., and R. L. Modlin. 1994. Cytokine patterns at the site of mycobacterial 64. Ghigo, E., A. Honstettre, C. Capo, J. P. Gorvel, D. Raoult, and J. L. Mege. 2004. Link infection. Immunobiology 191: 378–387. between impaired maturation of phagosomes and defective Coxiella burnetii killing in 59. Bleharski, J. R., H. Li, C. Meinken, T. G. Graeber, M. T. Ochoa, M. Yamamura, patients with chronic Q fever. J. Infect. Dis. 190: 1767–1772. A. Burdick, E. N. Sarno, M. Wagner, M. Rollinghoff, et al. 2003. Use of genetic profiling in leprosy to discriminate clinical forms of the disease. Science 301: 65. Meghari, S., Y. Bechah, C. Capo, H. Lepidi, D. Raoult, P. J. Murray, and J. L. Mege. 1527–1530. 2008. Persistent Coxiella burnetii infection in mice overexpressing IL-10: an efficient 60. Lee, D. J., P. A. Sieling, M. T. Ochoa, S. R. Krutzik, B. Guo, M. Hernandez, model for chronic Q fever pathogenesis. PLoS Pathog. 4: e23. T. H. Rea, G. Cheng, M. Colonna, and R. L. Modlin. 2007. LILRA2 activation in- 66. Meghari, S., C. Berruyer, H. Lepidi, F. Galland, P. Naquet, and J. L. Mege. 2007. hibits dendritic cell differentiation and to T cells. J. Immunol. Vanin-1 controls granuloma formation and macrophage polarization in Coxiella bur- 179: 8128–8136. netii infection. Eur. J. Immunol. 37: 24–32. 61. Krutzik, S. R., B. Tan, H. Li, M. T. Ochoa, P. T. Liu, S. E. Sharfstein, T. G. Graeber, 67. Benoit, M., E. Ghigo, C. Capo, D. Raoult, and J. L. Mege. 2008. The uptake of P. A. Sieling, Y. J. Liu, T. H. Rea, et al. 2005. TLR activation triggers the rapid dif- ferentiation of monocytes into macrophages and dendritic cells. Nat. Med. 11: apoptotic cells drives Coxiella burnetii replication and macrophage polarization: a 653–660. model for Q fever endocarditis. PLoS Pathog. 4: e1000066. 62. Waldmann, T. A., and Y. Tagaya. 1999. The multifaceted regulation of interleu- 68. Desnues, B., H. Lepidi, D. Raoult, and J. L. Mege. 2005. Whipple disease: intestinal kin-15 expression and the role of this cytokine in NK cell differentiation and host infiltrating cells exhibit a transcriptional pattern of M2/alternatively activated macro- response to intracellular pathogens. Annu. Rev. Immunol. 17: 19–49. phages. J. Infect. Dis. 192: 1642–1646. Downloaded from http://www.jimmunol.org/ by guest on September 24, 2021