Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-γ-dependent elimination of Paneth cells

Raetz, Megan; Hwang, Sun Hee; Wilhelm, Cara L.; Kirkland, Donna; Benson, Alicia; Sturge, Carolyn R.; Mirpuri, Julie; Vaishnava, Shipra; Hou, Baidong; DeFranco, Anthony L.; Gilpin, Christopher J.; Hooper, Lora V.; Yarovinsky, Felix

doi:10.1038/ni.2508

Cited by 183 publications

(233 citation statements)

References 46 publications

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“…A20 deficiency in IECs does not cause spontaneous Paneth cell defects, but sensitizes their apoptotic loss in inflammatory conditions, either by direct low-dose TNF exposure or by exposure to cytokines produced by hyperactive A20-deficient myeloid cells, including TNF and IFNg. Both these cytokines are well known for their cytotoxic activities on IECs and may contribute to the development of intestinal inflammation through their direct activity on Paneth cells [39][40][41] . Also goblet cells are severely affected in A20 IEC/myel-KO mice, compromising the protective epithelial mucus layer.…”

Section: Discussionmentioning

confidence: 99%

A20 controls intestinal homeostasis through cell-specific activities

et al. 2014

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The transcription factor NF-kB is indispensable for intestinal immune homeostasis, but contributes to chronic inflammation and inflammatory bowel disease (IBD). A20, an inhibitor of both NF-kB and apoptotic signalling, was identified as a susceptibility gene for multiple inflammatory diseases, including IBD. Despite absence of spontaneous intestinal inflammation in intestinal epithelial cell (IEC) specific A20 knockout mice, we found additional myeloid-specific A20 deletion to synergistically drive intestinal pathology through cell-specific mechanisms. A20 ensures intestinal barrier stability by preventing cytokine-induced IEC apoptosis, while A20 prevents excessive cytokine production in myeloid cells. Combining IEC and myeloid A20 deletion induces ileitis and severe colitis, characterized by IEC apoptosis, Paneth and goblet cell loss, epithelial hyperproliferation and intestinal microbiota dysbiosis. Continuous epithelial cell death and regeneration in an inflammatory environment sensitizes cells for neoplastic transformation and the development of colorectal tumours in aged mice.

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Section: Discussionmentioning

confidence: 99%

A20 controls intestinal homeostasis through cell-specific activities

et al. 2014

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“…Germ-free C57BL/6 mice have been described previously. 47,48 Igha -/-mice were initially purchased from Jackson Laboratory and bred for 3 generations in our animal facility prior to experimentation to ensure a stable microbiota composition within the environment of our animal facility. Myd88 -/-mice were generously provided by S. Akira and have been described previously in experimental colitis studies.…”

Section: Methodsmentioning

confidence: 99%

Proteobacteria-specific IgA regulates maturation of the intestinal microbiota

et al. 2013

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“…In addition to TLRs, IL-1R-mediated activation of MyD88 is indispensable for host resistance to intracellular pathogens (46) although IL-1R regulation of IFN-γ production is not completely understood, because IL-1R contributes to but is not absolutely essential for the IL-12 and IFN-γ production by DCs and NK cells, respectively (29,47). IL-1R or caspase-1 deficiency during T. gondii infection has no effect on IFN-γ production by T cells (47,48). IL-12-independent functions of MyD88 are also supported by the inability of recombinant IL-12 to rescue T. gondii-infected MyD88 −/− mice (16).…”

Section: Treatment Of Neutrophil-depleted Tlr11mentioning

confidence: 99%

TLR-independent neutrophil-derived IFN-γ is important for host resistance to intracellular pathogens

Sturge¹,

Benson²,

Raetz³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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IFN-γ is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-γ by natural killer and T cells is initiated by the recognition of pathogens by Toll-like receptors (TLRs). In an experimental model of toxoplasmosis, we have identified the presence of a nonlymphoid source of IFN-γ that was particularly evident in the absence of TLR-mediated recognition of Toxoplasma gondii . Genetically altered mice lacking all lymphoid cells due to deficiencies in Recombination Activating Gene 2 and IL-2Rγ c genes also produced IFN-γ in response to the protozoan parasite. Flow-cytometry and morphological examinations of non-NK/non-T IFN-γ + cells identified neutrophils as the cell type capable of producing IFN-γ. Selective elimination of neutrophils in TLR11 −/− mice infected with the parasite resulted in acute susceptibility similar to that observed in IFN-γ–deficient mice. Similarly, Salmonella typhimurium infection of TLR-deficient mice induces the appearance of IFN-γ + neutrophils. Thus, neutrophils are a crucial source for IFN-γ that is required for TLR-independent host protection against intracellular pathogens.

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Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-γ-dependent elimination of Paneth cells

Cited by 183 publications

References 46 publications

A20 controls intestinal homeostasis through cell-specific activities

A20 controls intestinal homeostasis through cell-specific activities

Proteobacteria-specific IgA regulates maturation of the intestinal microbiota

TLR-independent neutrophil-derived IFN-γ is important for host resistance to intracellular pathogens

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