Macrophage-specific expression of Arginase-1 is commonly believed to promote inflammation, fibrosis, and wound healing by enhancing L-proline, polyamine, and Th2 cytokine production. Here, however, we show that macrophage-specific Arg1 functions as an inhibitor of inflammation and fibrosis following infection with the Th2-inducing pathogen Schistosoma mansoni. Although susceptibility to infection was not affected by the conditional deletion of Arg1 in macrophages, Arg1 −/flox ;LysMcre mice died at an accelerated rate. The mortality was not due to acute Th1/NOS2-mediated hepatotoxicity or endotoxemia. Instead, granulomatous inflammation, liver fibrosis, and portal hypertension increased in infected Arg1 −/flox ;LysMcre mice. Similar findings were obtained with Arg1 flox/flox ;Tie2cre mice, which delete Arg1 in all macrophage populations. Production of Th2 cytokines increased in the infected Arg1 −/flox ;LysMcre mice, and unlike alternatively activated wild-type macrophages, Arg1 −/flox ;LysMcre macrophages failed to inhibit T cell proliferation in vitro, providing an underlying mechanism for the exacerbated Th2 pathology. The suppressive activity of Arg1-expressing macrophages was independent of IL-10 and TGF-β1. However, when exogenous L-arginine was provided, T cell proliferation was restored, suggesting that Arg1-expressing macrophages deplete arginine, which is required to sustain CD4+ T cell responses. These data identify Arg1 as the essential suppressive mediator of alternatively activated macrophages (AAM) and demonstrate that Arg1-expressing macrophages function as suppressors rather than inducers of Th2-dependent inflammation and fibrosis.

Toll-like receptor (TLR) signaling in macrophages is required for antipathogen responses, including the biosynthesis of nitric oxide from arginine, and is essential for immunity to Mycobacterium tuberculosis, Toxoplasma gondii and other intracellular pathogens. Here we report a ‘loophole’ in the TLR pathway that is advantageous to these pathogens. Intracellular pathogens induced expression of the arginine hydrolytic enzyme arginase 1 (Arg1) in mouse macrophages through the TLR pathway. In contrast to diseases dominated by T helper type 2 (TH2) responses, TLR-mediated Arg1 induction was independent of the TH2-associated STAT6 pathway. Specific elimination of Arg1 in macrophages favored host survival in T. gondii infection and decreased lung bacterial load in tuberculosis infection.

Waterborne parasitic diseases plague tropical regions of the world with the development of water resources often increasing transmission. Skin-penetrating cercariae (infectious stages of schistosome parasites) mature within their mammalian host, form sexual pairs and produce several hundred eggs per day. Many eggs are swept within the circulation and in the case of Schistosoma mansoni and S. japonicum, become lodged within hepatic sinusoids, invoking a fibrotic granulomatous response. Animal studies have identified a moderate type 1 helper (Th1) response to parasite antigens; however, a robust Th2 response to egg-derived antigens dominates and propagates fibrogenesis within the liver. Elegant T helper cell polarization studies have highlighted that critical control of Th1, Th2 and interleukin (IL)-17-secreting lymphocytes is necessary to prevent severe liver pathology. Alternatively activated macrophages develop in the Th2 milieu and upregulate Fizz1, Ym-1 and Arg-1. The possible contribution of macrophages to fibrogenesis and their role in immune regulation are discussed. Within the liver, natural (CD4 + CD25 + Forkhead box protein 3 (Foxp3) + ) and inducible (CD4 + Foxp3 -) Treg's are recruited, providing an essential regulatory arm to stabilize the immune response and limit immunopathology. This review ties together current thinking of how the granulomatous response develops, causing much of the associated immunopathology, with extensive discussions on how regulatory cells and cytokine decoy receptors serve to limit the extent of immune-mediated pathology during schistosomiasis.

Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla−/− mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla−/− mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla−/− mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla−/− mice developed stronger Th2 responses, which could be reversed by exogenous rRelmα treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-γ, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.

IntroductionThe IL-21 receptor (IL-21R) is a newly discovered member of the class I cytokine receptor family (1, 2). The receptor shows significant sequence and structural homology with the IL-4Rα chain and is adjacent to the IL-4Rα in the human and mouse genomes, while its ligand, IL-21, shares significant homology with the cytokines IL-2, 4). IL-21 and IL-21R are thus newly described members of the γ chain-dependent cytokine network because of their homology with cytokines and receptors that require the γ chain for functional signaling (5). Because all members of the γ chain network exhibit important and unique roles in host immunity, there has been growing interest in dissecting the novel functions of the IL-21R during antigen-triggered immune responses in vivo.Initial studies examining its function showed that IL-21 antagonizes NK cell expansion, yet it promotes antigen-specific T cell immunity including antitumor immunity (6-8), findings that suggested IL-21 can bridge innate and adaptive immune responses (9). IL-21 also regulates B cell and CD8 + T cell function in vivo (10-15). Additional studies suggested that IL-21 is a Th2 cytokine that can inhibit the differentiation of naive Th cells into IFN-γ-secreting

The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (T H 2)-mediated disease and associates with either the common γ-chain to form the type I IL-4R or with the IL-13R α1 chain (IL-13Rα1) to form the type II IL-4R. Here we used Il13ra1 −/− mice to characterize the distinct functions of type I and type II IL-4 receptors in vivo. In contrast to Il4ra −/− mice, which have weak T H 2 responses, Il13ra1 −/− mice had exacerbated T H 2 responses. Il13ra1−/− mice showed much less mortality after infection with Schistosoma mansoni and much more susceptibility to Nippostrongylus brasiliensis. IL-13Rα1 was essential for allergen-induced airway hyperreactivity and mucus hypersecretion but not for fibroblast or alternative macrophage activation. Thus, type I and II IL-4 receptors exert distinct effects on immune responses.Interleukin 4 (IL-4) and IL-13 are T helper type 2 (T H 2) cytokines with pleiotropic functions in immunity. They mediate resistance to many gastrointestinal parasites 1 and promote allergic inflammation 2,3 , asthma 4 and fibrosis 5 . IL-4 and IL-13 exert a wide range of effects on many cell types, including macrophages, fibroblasts, eosinophils, mast cells, natural killer cells, B cells and T cells 6 . IL-4 and IL-13 bind to and send signals through receptors composed of various combinations of four receptor subunits: IL-4Rα, IL-13Rα1, IL-13Rα2 and the common © 2007 Nature Publishing GroupCorrespondence should be addressed to T.A.W. (E-mail: twynn@niaid.nih.gov). AUTHOR CONTRIBUTIONS T.R.R. designed and did experiments and contributed to the manuscript; J.T.P., F.S., M.M.M.-K. and M.S.W. designed and did experiments; A.W.C. and J.F.U. assisted in animal experiments, scoring and data analysis; S.S., D.M.V., A.J.M. and G.D.Y. provided the Il13ra1 −/− mice and assisted in writing the manuscript; R.P.D. designed and assisted in experiments; and T.A.W. designed and supervised the project, designed and assisted in experiments, and helped write the manuscript. COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/natureimmunology/.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript γ-chain. The type I IL-4 receptor, a heterodimer of IL-4Rα and the common γ-chain, mediates IL-4-dependent activation of the transcription factor STAT6 in hematopoietic cells and is thus mostly responsible for the population expansion of CD4 + T H 2 cells. The type II IL-4 receptor, a heterodimer of IL-4Rα and IL-13Rα1 chains, can bind both IL-4 and IL-13 and is thought to be the main route by which nonhematopoietic cells respond to these cytokines 7 . Finally, the IL-13Rα2 chain binds IL-13 with high affinity and functions as a 'decoy receptor' 8 , although a report has suggested it can also show STAT6-independent signaling activity 9 .Because IL-4Rα fu...

Infection with the parasitic helminth Schistosoma mansoni causes significant liver fibrosis and extracellular matrix (ECM) remodeling. Matrix metalloproteinases (MMP) are important regulators of the ECM by regulating cellular inflammation, extracellular matrix deposition, and tissue reorganization. MMP12 is a macrophage-secreted elastase that is highly induced in the liver and lung in response to S. mansoni eggs, confirmed by both DNA microarray and real-time PCR analysis. However, the function of MMP12 in chronic helminth-induced inflammation and fibrosis is unclear. In this study, we reveal that MMP12 acts as a potent inducer of inflammation and fibrosis after infection with the helminth parasite S. mansoni. Surprisingly, the reduction in liver and lung fibrosis in MMP12-deficient mice was not associated with significant changes in cytokine, chemokine, TGF-β1, or tissue inhibitors of matrix metalloproteinase expression. Instead, we observed marked increases in MMP2 and MMP13 expression, suggesting that Mmp12 was promoting fibrosis by limiting the expression of specific ECM-degrading MMPs. Interestingly, like MMP12, MMP13 expression was highly dependent on IL-13 and type II–IL-4 receptor signaling. However, in contrast to MMP12, expression of MMP13 was significantly suppressed by the endogenous IL-13 decoy receptor, IL-13Rα2. In the absence of MMP12, expression of IL-13Rα2 was significantly reduced, providing a possible explanation for the increased IL-13-driven MMP13 activity and reduced fibrosis. As such, these data suggest important counter-regulatory roles between MMP12 and ECM-degrading enzymes like MMP2, MMP9, and MMP13 in Th2 cytokine-driven fibrosis.

Toll-like receptor (TLR) agonists induce potent innate immune responses and can be used in the development of novel vaccine adjuvants. However, access to TLRs can be challenging as exemplified by TLR 7, which is located intracellularly in endosomal compartments. To increase recognition and subsequent stimulatory effects of TLR 7, imiquimod was encapsulated in acetalated-dextran (Ac-DEX) microparticles. Ac-DEX, a water-insoluble and biocompatible polymer, is relatively stable at pH 7.4, but degrades rapidly under acidic conditions, such as those found in lysosomal vesicles. To determine the immunostimulatory capacity of encapsulated imiquimod, we compared the efficacy of free versus encapsulated imiquimod in activating RAW 264.7 macrophages, MH-S macrophages, and bone marrow derived dendritic cells. Encapsulated imiquimod significantly increased IL-1β, IL-6, and TNF-α cytokine expression in macrophages relative to the free drug. Furthermore, significant increases were observed in classic macrophage activation markers (iNOS, PD1-L1, and NO) after treatment with encapsulated imiquimod over the free drug. Also, bone marrow derived dendritic cells produced significantly higher levels of IL-1β, IL-6, IL-12p70, and MIP-1α as compared to their counterparts receiving free imiquimod. These results suggest that encapsulation of TLR ligands within Ac-DEX microparticles results in increased immunostimulation and potentially better protection from disease when used in conjunction with vaccine formulations.