Soil transmitted helminth infections remain one of the most neglected groups of infectious diseases and one of the greatest public health challenges worldwide, with an estimated two billion people infected. Importantly, recovery from helminth infection involves not only clearance of the parasite, but also successful repair of the inflamed, damaged intestine in order to restore tissue protection and these mechanisms of tissue protection are often conserved across non-infectious intestinal diseases. Thus, the development of successful immuno- therapies against soil-transmitted helminth parasites requires a more comprehensive understanding of the mechanisms that regulate both infection-induced immunity and intestinal tissue protection. This proposal will interrogate the role of group 2 innate lymphoid cells (ILC2s) in promoting anti-helminth immunity and regulating infectious and non-infectious intestinal tissue protection via activation of the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) pathway. In preliminary studies, we found that deletion of AREG resulted in dysregulated immune responses, impaired worm expulsion and failed intestinal repair following helminth infection. Critically, the importance of this pathway was not limited to pathogen infection, as AREG expression was also elevated in a murine model of non-infectious intestinal damage, and disruption in AREG-EGFR interactions resulted in exacerbated intestinal inflammation and impaired intestinal repair. We further identified ILC2s as a key source of this growth factor and found that therapeutic transfer of ILC2s or AREG protein can limit inflammation and promote tissue protection in mice. Despite these advances, the factors that regulate intestinal AREG responses, the cell-intrinsic requirements for AREG expression, the downstream mechanisms by which AREG influences epithelial cell responses, and whether differential AREG expression in humans is associated with intestinal inflammation, all remain unknown. Employing new in vivo tools, this competitive grant renewal will focus on delineating: (i) the signals and cell-intrinsic requirements for AREG in promoting immunity to helminth infection and restoration of intestinal tissue protection, (ii) the mechanisms by which ILC2-AREG regulates intestinal epithelial cell (IEC) progenitors to promote tissue protection, and (iii), whether therapeutic delivery of rAREG can reverse established chronic intestinal tissue damage and inflammation and restore tissue protection. We anticipate that defining the mechanisms by which the ILC2-AREG-EGFR pathway regulates both intestinal immunity and tissue protection is critical for the design of new immunologic intervention strategies to treat and prevent helminth infections and non-infectious inflammatory diseases such as IBD. !
With infection rates estimated at two billion worldwide, intestinal helminth parasites remain one of the greatest public health and economic challenges globally. Successful recovery requires immune cell-mediated clearance of the parasite and repair of the damaged intestinal tissue to restore tissue protection, however the cellular and molecular mechanisms that can coordinately promote immunity and tissue protection following infectious or non-infectious insults in the intestine remain poorly understood. This proposal will interrogate how group 2 innate lymphoid cells (ILC2s) regulate intestinal immunity and tissue protection through activation of the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) pathway.
|Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure et al. (2018) ?2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359:1056-1061|
|Veiga-Fernandes, Henrique; Artis, David (2018) Neuronal-immune system cross-talk in homeostasis. Science 359:1465-1466|
|Meisel, Jacquelyn S; Sfyroera, Georgia; Bartow-McKenney, Casey et al. (2018) Commensal microbiota modulate gene expression in the skin. Microbiome 6:20|
|Chu, Coco; Moriyama, Saya; Li, Zhi et al. (2018) Anti-microbial Functions of Group 3 Innate Lymphoid Cells in Gut-Associated Lymphoid Tissues Are Regulated by G-Protein-Coupled Receptor 183. Cell Rep 23:3750-3758|
|Klose, Christoph S N; Mahlakõiv, Tanel; Moeller, Jesper B et al. (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549:282-286|
|Blander, J Magarian; Longman, Randy S; Iliev, Iliyan D et al. (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851-860|
|Wallrapp, Antonia; Riesenfeld, Samantha J; Burkett, Patrick R et al. (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351-356|
|Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure et al. (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656-65|
|Alex, Aneesh; Tait Wojno, Elia D; Artis, David et al. (2016) Label-Free Imaging of Eosinophilic Esophagitis Mouse Models Using Optical Coherence Tomography. Methods Mol Biol 1422:127-36|
|Rak, Gregory D; Osborne, Lisa C; Siracusa, Mark C et al. (2016) IL-33-Dependent Group 2 Innate Lymphoid Cells Promote Cutaneous Wound Healing. J Invest Dermatol 136:487-496|
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