CD40 contributes to lethality in acute sepsis: in vivo role for CD40 in innate immunity.
Sepsis induces an early inflammatory cascade initiated by the innate immune response. This often results in the development of multisystem organ failure. We examined the role of CD40, a costimulatory molecule that is integral in adaptive immunity, by using a murine model of polymicrobial sepsis. CD40 knockout (KO) mice had delayed death and improved survival after cecal ligation and puncture (CLP). In addition, they had less remote organ injury as manifested by reduced pulmonary capillary leakage. The improvements in survival and remote organ dysfunction in CD40 KO mice were associated with reduced interleukin-6 (IL-6) and IL-10 levels in serum and bronchoalveolar lavage fluid compared to the levels in wild-type (WT) controls. Furthermore, in contrast to WT mice, CD40 KO mice had no induction of the Th1 cytokines IL-12 and gamma interferon in serum or lungs after CLP. The alterations in cytokine production in CD40 KO mice were associated with similar changes in transcription factor activity. After CLP, CD40 KO mice had attenuated activation of nuclear factor kappaB and signal transducer and activator of transcription 3 in both the lung and the liver. Finally, WT mice had increased expression of CD40 on their alveolar macrophages. These data highlight the importance of CD40 activation in the innate immune response during polymicrobial sepsis and the subsequent development of remote organ dysfunction.
Gold
Jeffrey A
JA
Division of Pulmonary and Critical Care Medicine, New York University Medical Center, New York 10016, USA.
Parsey
Merdad
M
Hoshino
Yoshihiko
Y
Hoshino
Satomi
S
Nolan
Anna
A
Yee
Herman
H
Tse
Doris B
DB
Weiden
Michael D
MD
D000208:Acute Disease; D000818:Animals; D019013:CD40 Antigens / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor; D018805:Sepsis / Q000276:immunology* / Q000401:mortality; D015534:Trans-Activators / Q000378:metabolism
D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D004247:DNA