CD137 expressed on neutrophils plays dual roles in antibacterial responses against Gram-positive and Gram-negative bacterial infections

Severe sepsis and septic shock caused mainly by bacterial infections are life-threatening conditions that urge the development of novel therapies. However, host responses to and pathophysiology of sepsis have not been clearly understood, which remains a major obstacle for the development of effective therapeutics. Recently, we have shown that stimulation of a costimulatory molecule, CD137, enhanced survival of mice infected with the Gram-positive (G + ) intracellular bacterium Listeria monocytogenes but decreased survival in a polymicrobial sepsis model. Herein, we report that CD137 deficiency or blocking of CD137 signaling decreased antibacterial responses of mice infected with G + bacteria ( Staphylococcus aureus , Streptococcus pneumoniae , and Enterococcus faecalis ) but increased these responses in mice infected with Gram-negative (G − ) bacteria ( Escherichia coli , Pseudomonas aeruginosa , and Salmonella enterica serovar Typhimurium). Consistent with these findings, stimulation of CD137 by administration of agonistic antibody enhanced responses against G + bacteria, whereas it decreased these responses against G − bacteria. Neutrophils were responsible for CD137-mediated opposite roles in control of G + and G − bacterial infections. Stimulation of CD137 enhanced activities of neutrophils against S. aureus but decreased these activities against E. coli , while CD137 blocking produced opposite results with the stimulation of CD137 in vivo and in vitro . Furthermore, we found that combined signaling of CD137 and Toll-like receptor 2 (TLR2) induced synergistic production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) by neutrophils, but combined signaling of CD137 and TLR4 did not. Our data strongly suggest that CD137 may play a dual role in sepsis in association with TLRs.