title: CD137 expressed on neutrophils plays dual roles in antibacterial responses against Gram-positive and Gram-negative bacterial infections.
abstract: 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.
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
authors.forename: Quang-Tam
authors.initials: QT
authors.lastname: Nguyen
authors.forename: Thu-Ha T
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Seong-A
authors.initials: SA
authors.lastname: Ju
authors.forename: Yea-Sol
authors.initials: YS
authors.lastname: Lee
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Han
authors.forename: Sang-Chul
authors.initials: SC
authors.lastname: Lee
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
authors.forename: Rina
authors.initials: R
authors.lastname: Yu
authors.forename: Gyu Yeol
authors.initials: GY
authors.lastname: Kim
authors.forename: Byung Ju
authors.initials: BJ
authors.lastname: Lee
authors.forename: Byung-Sam
authors.initials: BS
authors.lastname: Kim
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006090:Gram-Negative Bacteria / Q000276:immunology; D016905:Gram-Negative Bacterial Infections / Q000276:immunology*; D006094:Gram-Positive Bacteria / Q000276:immunology; D016908:Gram-Positive Bacterial Infections / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism*; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism*
chemical_list: D016207:Cytokines; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
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