NK but Not CD1-Restricted NKT Cells Facilitate Systemic Inflammation during Polymicrobial Intra-Abdominal Sepsis

Abstract

Evidence suggests that NK and NKT cells contribute to inflammation and mortality during septic shock caused by cecal ligation and puncture (CLP). However, the specific contributions of these cell types to the pathogenesis of CLP-induced septic shock have not been fully defined. The goal of the present study was to determine the mechanisms by which NK and NKT cells mediate the host response to CLP. Control, NK cell-deficient, and NKT cell-deficient mice underwent CLP. Survival, cytokine production, and bacterial clearance were measured. NK cell trafficking and interaction with myeloid cells was also studied. Results show that mice treated with anti-asialoGM1 (NK cell deficient) or anti-NK1.1 (NK/NKT cell deficient) show less systemic inflammation and have improved survival compared with IgG-treated controls. CD1 knockout mice (NKT cell deficient) did not demonstrate decreased cytokine production or improved survival compared with wild type mice. Trafficking studies show migration of NK cells from blood and spleen into the inflamed peritoneal cavity where they appear to facilitate the activation of peritoneal macrophages (F4-80+GR-1−) and F4-80+Gr-1+ myeloid cells. These findings indicate that NK but not CD1-restricted NKT cells contribute to acute CLP-induced inflammation. NK cells appear to mediate their proinflammatory functions during septic shock, in part, by migration into the peritoneal cavity and amplification of the proinflammatory activities of specific myeloid cell populations. These findings provide new insights into the mechanisms used by NK cells to facilitate acute inflammation during septic shock.

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

“…Several studies have demonstrated that NKT cells promote LPS-or cecal ligation and puncture (CLP)-induced sepsis in mice through the production of IFN-γ [8][9][10]. Consistent with these findings, two independent studies have demonstrated that treatment of C57BL/6 mice with anti-CD1d antibody enhances survival rates during CLP-induced sepsis [11,12], suggesting that NKT-cell-mediated promotion of sepsis depends on an interaction between CD1d and TCRs of NKT cells.…”

“…Consistent with these findings, two independent studies have demonstrated that treatment of C57BL/6 mice with anti-CD1d antibody enhances survival rates during CLP-induced sepsis [11,12], suggesting that NKT-cell-mediated promotion of sepsis depends on an interaction between CD1d and TCRs of NKT cells. In contrast, Etogo et al found that CD1d −/− mice did not exhibit improved survival in CLP-induced sepsis [10]. Furthermore, Jα18 −/− mice are more susceptible to shock than their heterozygous littermates and treatment of WT mice with α-galactosylceramide (α-GalCer), a surrogate CD1d ligand, protects them from LPS-induced shock by enhancing IL-10 and IL-4 production by NKT cells [13,14], indicating that NKT cells attenuate LPS-induced shock.…”

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

“…In this study, however, depletion of NK cells by anti-asialo GM1 antibodies did not significantly modify the survival curves. In contrast, NK cells contribute to the overzealous production of inflammatory cytokines associated with mortality of septic shock (86,184). Most interestingly, in the latter study, the beneficial effect of the deletion of NK cells by either anti-asialo GM1 or anti-NK1.1 antibodies was only seen when mice were treated with antibiotics.…”

Lipopolysaccharide-Mediated Mast Cell Activation Induces IFN-γ Secretion by NK Cells

“…In addition to MCs, NK cells have been implicated in models of sepsis. NK cells are a major source of IFN-g in endotoxin-induced sepsis (46)(47)(48)(49)(50). Etogo et al (46) have recently described that NK cell numbers and activation increase in the peritoneal cavity after cecal ligation and puncture.…”