The Role of Hepatic Invariant NKT Cells in Systemic/Local Inflammation and Mortality during Polymicrobial Septic Shock

Abstract

NKT cells have been described as innate regulatory cells because of their rapid response to conserved glycolipids presented on CD1d via their invariant TCR. However, little is known about the contribution of the hepatic NKT cell to the development of a local and/or systemic immune response to acute septic challenge (cecal ligation and puncture (CLP)). We found not only that mice deficient in invariant NKT cells (Jα18−/−) had a marked attenuation in CLP-induced mortality, but also exhibited an oblation of the systemic inflammatory response (with little effect on splenic/peritoneal immune responsiveness). Flow cytometric data indicated that following CLP, there was a marked decline in the percentage of CD3+α-galactosylceramide CD1d tetramer+ cells in the mouse C57BL/6J and BALB/c liver nonparenchymal cell population. This was associated with the marked activation of these cells (increased expression of CD69 and CD25) as well as a rise in the frequency of NKT cells positive for both Th1 and Th2 intracellular cytokines. In this respect, when mice were pretreated in vivo with anti-CD1d-blocking Ab, we observed not only that this inhibited the systemic rise of IL-6 and IL-10 levels in septic mice and improved overall septic survival, but that the CLP-induced changes in liver macrophage IL-6 and IL-10 expressions were inversely effected by this treatment. Together, these findings suggest that the activation of hepatic invariant NKT cells plays a critical role in regulating the innate immune/systemic inflammatory response and survival in a model of acute 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. In contrast, Etogo et al found that CD1d −/− mice did not exhibit improved survival in CLP-induced sepsis [10].…”

NKT Cells: The Culprits of Sepsis?

“…Additional depletion of NK cells by antiasialoGM1 antibody conferred complete resistance to septic mortality and was associated with diminished pro-inflammatory cytokine synthesis and secretion [45]. Similarly, Ja18 -/-mice were used to show that iNKT cell deficiency significantly decreased septic mortality and ameliorated the systemic proinflammatory response [46]. Despite contradictory findings on the relative contribution of iNKT cells to a Th1 or Th2 response, these results consistently implicate a detrimental effect of NKT cell activation in polymicrobial sepsis.…”

Sulfatide Attenuates Experimental Staphylococcus aureus Sepsis through a CD1d-Dependent Pathway

“…Mice lacking type I NKT cells had lower levels of circulating gamma interferon (IFN-␥) and TNF-␣ and increased survival in the generalized Shwartzman reaction (20). Studies of polymicrobial septic shock provide divergent data; J␣18-deficient C57BL/6J mice lacking type I NKT cells showed an increased survival level and decreased levels of proinflammatory cytokines in the serum (21), while another study found that CD1d-deficient mice lacking all NKT cells did not differ from WT mice in septic mortality and induction of proinflammatory cytokines (37). In the S. aureus model of sepsis studied here, despite the activation of type I NKT cells by the bacterial injection, there was no significant difference in mortality rate in mice lacking type I NKT cells (J␣18 Ϫ/Ϫ ) or in CD1d-deficient mice compared to their heterozygote littermates.…”

“…Initial studies pointed to a detrimental role of NKT cells in sepsis by magnifying damage and increasing mortality (20)(21)(22)(23)(24). However, those studies either did not discriminate between type I and type II NKT cells (22)(23)(24) or focused exclusively on type I cells (20,21).…”

“…Information about the relative activities of the two types of NKT cells in sepsis therefore is not available. Moreover, previous studies used models of Gramnegative septic shock (20,22) and polymicrobial, predominantly Gram-negative sepsis (21,23,24). A significant proportion of hospital cases of sepsis is due to Gram-positive cocci, which induce a different inflammatory response from that of Gram-negative bacteria (25).…”