Abstract
BackgroundInflammation in the early stages of sepsis is governed by the innate immune response. Costimulatory molecules are a receptor/ligand class of molecules capable of regulation of inflammation in innate immunity via macrophage/neutrophil contact. We recently described that CD80/86 ligation is required for maximal macrophage activation and CD80/86−/− mice display reduced mortality and inflammatory cytokine production after cecal ligation and puncture (CLP). However, these data also demonstrate differential regulation of CD80 and CD86 expression in sepsis, suggesting a divergent role for these receptors. Therefore, the goal of this study was to determine the individual contribution of CD80/86 family members in regulating inflammation in sepsis.Methodology/Principal FindingsCD80−/− mice had improved survival after CLP when compared to WT or CD86−/− mice. This was associated with preferential attenuation of inflammatory cytokine production in CD80−/− mice. Results were confirmed with pharmacologic blockade, with anti-CD80 mAb rescuing mice when administered before or after CLP. In vitro, activation of macrophages with neutrophil lipid rafts caused selective disassociation of IRAK-M, a negative regulator of NF-κB signaling from CD80; providing a mechanism for preferential regulation of cytokine production by CD80. Finally, in humans, upregulation of CD80 and loss of constitutive CD86 expression on monocytes was associated with higher severity of illness and inflammation confirming the findings in our mouse model.ConclusionsIn conclusion, our data describe a differential role for CD80 and CD86 in regulation of inflammation in the innate immune response to sepsis. Future therapeutic strategies for blockade of the CD80/86 system in sepsis should focus on direct inhibition of CD80.
Highlights
Sepsis, the systemic inflammatory response to infection (SIRS), is a devastating condition affecting nearly 750,000 people/year and resulting in over $17billion/year in health care expenditure [1,2]
In conclusion, our data describe a differential role for CD80 and CD86 in regulation of inflammation in the innate immune response to sepsis
We first wished to establish that CD28 was serving as the predominant ligand for CD80 or CD86 engagement in sepsis
Summary
The systemic inflammatory response to infection (SIRS), is a devastating condition affecting nearly 750,000 people/year and resulting in over $17billion/year in health care expenditure [1,2]. The innate immune response forms the corner stone of regulation of inflammation and pathogen control in sepsis This is characterized by an initial burst of pro-inflammatory cytokines, such as IL-6, TNF-a and IL-1b, which in controlled settings, can recapitulate many of the clinical findings of sepsis. We recently described that CD80/86 ligation is required for maximal macrophage activation and CD80/862/2 mice display reduced mortality and inflammatory cytokine production after cecal ligation and puncture (CLP). These data demonstrate differential regulation of CD80 and CD86 expression in sepsis, suggesting a divergent role for these receptors. The goal of this study was to determine the individual contribution of CD80/86 family members in regulating inflammation in sepsis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
