Blockade of CD137 Signaling Counteracts Polymicrobial Sepsis Induced by Cecal Ligation and Puncture

ABSTRACTSepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Previously, we have shown that CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, plays critical roles in eradicating infectiveListeria monocytogenes, a gram-positive bacterium, and that stimulation of CD137 protects mice from sepsis-induced death. In this study, we unexpectedly found that CD137 activation aggravated polymicrobial sepsis due to mixed gram-positive and gram-negative bacterial infection induced by cecal ligation and puncture (CLP). CD137-deficient (CD137−/−) mice showed significantly lower mortality than CD137-sufficient (CD137+/+) mice in the CLP model. Administration of an agonistic anti-CD137 monoclonal antibody (MAb) to CD137+/+mice decreased their survival in this infection model, while administration of a blocking anti-CD137 ligand MAb (TKS-1) to such mice increased their survival. CD137−/−mice and TKS-1-treated CD137+/+mice had lower levels of chemokines/proinflammatory cytokines (monocyte chemoattractant protein 1, interleukin-6 [IL-6], tumor necrosis factor alpha, IL-12) and an anti-inflammatory cytokine (IL-10), exhibited improved bacterial clearance in the peritoneum, liver, and blood, and had greater numbers of infiltrated peritoneal neutrophils and macrophages in the CLP model than control mice. Our data suggest that CD137 activation aggravates polymicrobial sepsis induced by CLP.