(The) role of NOD2 in cecal ligation and puncture(CLP) induced sepsis

Abstract

Sepsis is a dysregulated inflammatory disease that causes multiple organ failure. Nucleotide-binding oligomerization domain (NOD)2 is a cytosolic protein that triggers innate immune responses by sensing bacterial peptidoglycans. However, NOD2 function in sepsis is unknown. To address this issue, the cecum was ligated and punctured in WT and NOD2-/- mice. Bacterial CFUs, and serum and peritoneal C5a levels were lower in NOD2-/- mice compared to WT mice. Phagocytosis and cytokine production by peritoneal cells against LPS were higher in NOD2-/- mice, thereby increasing survival. Adoptive transfer of NOD2-deficient, but not WT splenocytes, increased survival rates of WT mice with Gr-1+ cell depletion, suggesting that NOD2 expression in Gr-1+ granulocytes is crucial for promoting sepsis. Ly-6G+ peritoneal cells produced IL-1 and IL-10, and serum and peritoneal levels were higher in WT mice as compared with NOD2-/- mice during sepsis. Administering recombinant IL-1 or IL-10 to NOD2-/- mice, but not WT, decreased peritoneal cell cytokine production against LPS and increased C5a levels, thereby decreasing survival rates. Recombinant C5a decreased survival rates in NOD2-/- mice, but not in WT. These findings suggest that NOD2 enhances IL-1 and IL-10 production by Ly-6G+ granulocytes, which deactivates immune cells and increases C5a levels, thereby aggravating sepsis.