In schistosomiasis and other diseases associated with type-2 immunity, the pathology resulting from chronic infection or chronic allergen exposure is predominantly induced by the host immune response. The chronic type-2 immune response eventually triggers significant fibrosis, which is the primary cause of morbidity and mortality in many chronic infectious and inflammatory diseasese . Our work is focused on elucidating the mechanisms of granulomatous inflammation and fibrosis. Progress was made in the following areas: 1) The type-2 associated protein acidic mammalian chitinase (AMCase) was found to control T. gondii cyst formation in the brain. Chronic infections represent a continuous battle between the host's immune system and pathogen replication. Many protozoan parasites have evolved a cyst lifecycle stage that provides it with increased protection from environmental degradation as well as endogenous host mechanisms of attack. In the case of Toxoplasma gondii, these cysts are predominantly found in the immune protected brain making clearance of the parasite more difficult and resulting in a lifelong infection. Currently, little is known about the nature of the immune response stimulated by the presence of these cysts or how they are able to propagate. In this study, we and our colleagues established a novel chitinase-dependent mechanism of cyst control in the infected brain. Despite a dominant Th1 immune response during Toxoplasma infection there exists a population of alternatively activated macrophages (AAM) in the infected CNS. These cells are capable of cyst lysis via the production of AMCase as revealed by live imaging, and this chitinase is necessary for protective immunity within the CNS. These data demonstrate chitinase activity in the brain in response to a protozoan pathogen and provide a novel mechanism to facilitate cyst clearance during chronic infections. 2) miR-182 and miR-10a were identified as key regulators of Treg specialisation and stability during Schistosome and Leishmania-associated inflammation. A diverse suite of effector immune responses provide protection against various pathogens. However, the array of effector responses must be immunologically regulated to limit pathogen- and immune-associated damage. CD4(+)Foxp3(+) regulatory T cells (Treg) calibrate immune responses;however, how Treg cells adapt to control different effector responses is unclear. To investigate the molecular mechanism of Treg diversity we used whole genome expression profiling and next generation small RNA sequencing of Treg cells isolated from type-1 or type-2 inflamed tissue following Leishmania major or Schistosoma mansoni infection, respectively. In-silico analyses identified two miRNA "regulatory hubs" miR-10a and miR-182 as critical miRNAs in Th1- or Th2-associated Treg cells, respectively. Functionally and mechanistically, in-vitro and in-vivo systems identified that an IL-12/IFNγaxis regulated miR-10a and its putative transcription factor, Creb. Importantly, reduced miR-10a in Th1-associated Treg cells was critical for Treg function and controlled a suite of genes preventing IFNγproduction. In contrast, IL-4 regulated miR-182 and cMaf in Th2-associed Treg cells, which mitigated IL-2 secretion, in part through repression of IL2-promoting genes. Together, this study indicates that CD4(+)Foxp3(+) cells can be shaped by local environmental factors, which orchestrate distinct miRNA pathways preserving Treg stability and suppressor function. 3) Macrophages were identified as IL-25/IL-33-responsive cells play and regulate type 2 immunity. Type 2 immunity is essential for host protection against nematode infection but is detrimental in allergic inflammation or asthma. There is a major research focus on the effector molecules and specific cell types involved in the initiation of type 2 immunity. Recent work has implicated an important role of epithelial-derived cytokines, IL-25 and IL-33, acting on innate immune cells that are believed to be the initial sources of type 2 cytokines IL-4/IL-5/IL-13. The identities of the cell types that mediate the effects of IL-25/IL-33, however, remain to be fully elucidated. In the present study, we demonstrate that macrophages as IL-25/IL-33-responsive cells play an important role in inducing type 2 immunity using both in vitro and in vivo approaches. Macrophages produced type 2 cytokines IL-5 and IL-13 in response to the stimulation of IL-25/IL-33 in vitro, or were the IL-13-producing cells in mice administrated with exogenous IL-33 or infected with Heligmosomoides bakeri. In addition, IL-33 induced alternative activation of macrophages primarily through autocrine IL-13 activating the IL-4Rα-STAT6 pathway. Moreover, depletion of macrophages attenuated the IL-25/IL-33-induced type 2 immunity in mice, while adoptive transfer of IL-33-activated macrophages into mice with a chronic Heligmosomoides bakeri infection induced worm expulsion accompanied by a potent type 2 protective immune response. Thus, macrophages represent a unique population of the innate immune cells pivotal to type 2 immunity and a potential therapeutic target in controlling type 2 immunity-mediated inflammatory pathologies. 4) The Role of arginase 1 from myeloid cells in th2-dominated lung inflammation was clarified. Th2-driven lung inflammation increases Arginase 1 (Arg1) expression in alternatively-activated macrophages (AAMs). AAMs modulate T cell and wound healing responses and Arg1 might contribute to asthma pathogenesis by inhibiting nitric oxide production, regulating fibrosis, modulating arginine metabolism and restricting T cell proliferation. We used mice lacking Arg1 in myeloid cells to investigate the contribution of Arg1 to lung inflammation and pathophysiology. In six model systems encompassing acute and chronic Th2-mediated lung inflammation we observed neither a pathogenic nor protective role for myeloid-expressed Arg1. The number and composition of inflammatory cells in the airways and lungs, mucus secretion, collagen deposition, airway hyper-responsiveness, and T cell cytokine production were not altered if AAMs were deficient in Arg1 or simultaneously in both Arg1 and NOS2. Our results argue that Arg1 is a general feature of alternative activation but only selectively regulates Th2 responses. Therefore, attempts to experimentally or therapeutically inhibit arginase activity in the lung should be examined with caution. 5) MyD88, STAT6, and IL-13 were shown to control murine intestinal function. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical "type 2" immune response in the gastrointestinal tract, yet the underlying mechanisms remain to be fully elucidated. In addition, the role of IL-33 in the regulation of gastrointestinal function is not known. We found that exogenous IL-33 induced a polarized type 2 cytokine response in the intestine that was entirely MyD88 dependent but STAT6 and IL-13 independent. Mice injected with recombinant IL-33 exhibited intestinal smooth muscle hypercontractility, decreased epithelial responses to acetylcholine and glucose, and increased mucosal permeability. IL-33 effects on intestinal epithelial function were STAT6 dependent, and both IL-4 and IL-13 appeared to play a role. The effects on smooth muscle function, however, were attributable to both STAT6-dependent and -independent mechanisms. In addition, IL-13 induction of insulin-like growth factor-1 was implicated in IL-33-induced smooth muscle hypertrophy. Finally, alternative activation of macrophages induced by IL-33 revealed a novel pathway that is IL-4 IL-13, and STAT6 independent. Thus manipulating IL-33 or related signaling pathways represents a novel therapeutic target in IBD

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Sun, Rex; Urban Jr, Joseph F; Notari, Luigi et al. (2016) Interleukin-13 Receptor α1-Dependent Responses in the Intestine Are Critical to Parasite Clearance. Infect Immun 84:1032-44
Wynn, Thomas A; Vannella, Kevin M (2016) Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity 44:450-62
Borthwick, L A; Barron, L; Hart, K M et al. (2016) Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis. Mucosal Immunol 9:38-55
Gieseck 3rd, Richard L; Ramalingam, Thirumalai R; Hart, Kevin M et al. (2016) Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis. Immunity 45:145-58
Vannella, Kevin M; Ramalingam, Thirumalai R; Hart, Kevin M et al. (2016) Acidic chitinase primes the protective immune response to gastrointestinal nematodes. Nat Immunol 17:538-44
Ramalingam, Thirumalai R; Gieseck, Richard L; Acciani, Thomas H et al. (2016) Enhanced protection from fibrosis and inflammation in the combined absence of IL-13 and IFN-γ. J Pathol 239:344-54
Weist, Brian M; Kurd, Nadia; Boussier, Jeremy et al. (2015) Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat Immunol 16:635-41
Tacke, Frank; Wynn, Thomas A (2015) Biomarker and Therapeutic Potential of CSF1 in Acute Liver Failure. Gastroenterology 149:1675-8
Wynn, Thomas A (2015) Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol 15:271-82
Spencer, S P; Wilhelm, C; Yang, Q et al. (2014) Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343:432-7

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