CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis

Anna Nolan, Michael Weiden, Ann Kelly, Yoshihiko Hoshino, Satomi Hoshino, Nehal Mehta, Jeffrey (Jeff) Gold

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Rationale: Costimulatory molecules, including the CD40-CD154 and CD80/86-CD28 dyads, play a prominent role in regulating inflammation in the adaptive immune response. Studies from our group and others suggest a potentially important role for these costimulatory cascades in innate immunity as well. Objectives: To determine the role of CD80/86 alone and in combination with CD40 in lethal polymicrobial sepsis in mice and humans. Methods: The murine cecal ligation and puncture (CLP) model was used to determine the role of CD80/86 alone and in combination with CD40 using wild-type mice, CD80/86 -/- mice, and novel CD40/80/86-/- mice. Expression of cell-bound and soluble costimulatory molecules was assessed in humans via ELISA and flow cytometry. Measurements and Main Results: Lethal CLP was associated with up-regulation of CD40 and CD80/86 and their respective ligands CD28 and CD154 on innate effector cells. Blockade or deletion of CD80/86 attenuated mortality and inflammatory cytokine production during CLP. CD40/80/86 -/- mice exhibited further reductions in mortality, lung injury, and inflammatory cytokine production compared with CD80/86-/- mice. Finally, humans with sepsis had increased monocyte expression of CD40 and CD80 compared with healthy control subjects; with higher levels in subjects requiring vasopressor support. Levels of soluble CD28 and CD154 were significantly higher in patients who died compared with those who lived. Conclusions: These data demonstrate a central role for CD40 and CD80/86 in the innateimmune response and suggest that combined inhibition of CD40 and CD80/86 may improve mortality in sepsis. Expression of costimulatory molecules may serve as biomarkers for outcome in septic patients.

Original languageEnglish (US)
Pages (from-to)301-308
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume177
Issue number3
DOIs
StatePublished - Feb 1 2008

Fingerprint

Sepsis
Inflammation
Mortality
Punctures
Ligation
Cytokines
Lung Injury
Adaptive Immunity
Innate Immunity
Monocytes
Healthy Volunteers
Flow Cytometry
Up-Regulation
Biomarkers
Enzyme-Linked Immunosorbent Assay
Ligands

Keywords

  • Costimulation
  • Innate immunity
  • Sepsis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis. / Nolan, Anna; Weiden, Michael; Kelly, Ann; Hoshino, Yoshihiko; Hoshino, Satomi; Mehta, Nehal; Gold, Jeffrey (Jeff).

In: American Journal of Respiratory and Critical Care Medicine, Vol. 177, No. 3, 01.02.2008, p. 301-308.

Research output: Contribution to journalArticle

Nolan, Anna ; Weiden, Michael ; Kelly, Ann ; Hoshino, Yoshihiko ; Hoshino, Satomi ; Mehta, Nehal ; Gold, Jeffrey (Jeff). / CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis. In: American Journal of Respiratory and Critical Care Medicine. 2008 ; Vol. 177, No. 3. pp. 301-308.
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