Natural killer cells protect mice from DSS-induced colitis by regulating neutrophil function via the NKG2A receptor

Abstract

Natural killer (NK) cells are traditionally considered in the context of tumor surveillance and infection defense but their role in chronic inflammatory disorders such as inflammatory bowel disease is less clear. Here, we investigated the role of NK cells in dextran sodium sulfate (DSS)-induced colitis in mice. Depletion of NK cells impairs the survival of mice with colitis and is linked with dramatic increases in colonic damage, leukocyte infiltration, and pro-inflammatory profiles. Mice depleted of NK cells had increased numbers of neutrophils in colons and mesenteric lymph nodes, compared with control mice, in addition to acquiring a hyper-activation status. In vitro and in vivo studies demonstrate that NK cells downregulate pro-inflammatory functions of activated neutrophils, including reactive oxygen species and cytokine production, by direct cell-to-cell contact involving the NK cell-inhibitory receptor NKG2A. Our results indicate an immunoregulatory mechanism of action of NK cells attenuating DSS-induced colitis neutrophil-mediated inflammation and tissue injury via NKG2A-dependent mechanisms.

A Novel Regulatory Macrophage Induced by a Helminth Molecule Instructs IL-10 in CD4+ T Cells and Protects against Mucosal Inflammation

“…Tracking of labeled AvCystatin-Mregs showed that they located to the lymph nodes draining the sites of inflammation as well as the spleen in both disease models. The complete protection against body-weight loss and suppressed colon pathology seen in recipients of a single transfer of AvCystatin-Mregs in the colitis model correlated with high frequencies of AvCystatin-Mregs migrating to the colon and lower numbers of MPO + cells (mostly neutrophils) and eosinophils contributing to tissue damage in the DSS model (31,32). Whether AvCystatin-Mregs trafficking to the colon in this model suppressed the production of chemoattractants for innate cells critically involved in mucosal inflammation during DSSinduced colitis remains to be investigated.…”

Human NK Cells Licensed by Killer Ig Receptor Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function

“…(7) However, due to the complex roles and functional proficiencies of NK cell subpopulations, the biologic mechanisms of their involvement in chronic inflammatory diseases, and the ones pertinent to inflammatory bowel disease, remain uncertain. (1–4, 8, 9)…”

Combined immunodeficiency with CD4 lymphopenia and sclerosing cholangitis caused by a novel loss-of-function mutation affecting IL21R

“…Recently, NK cells were shown to down-regulate pro-inflammatory functions of neutrophils thereby protecting against colitis in a mouse model. 17 Thus reduced NK-cell numbers in the index patient could contribute to the eosinophilic duodenitis, possibly caused by cryptosporidiosis.…”