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Sepsis-induced changes in macrophage co-stimulatory molecule expression: CD86 as a regulator of anti-inflammatory
Sarah Newton1, Yanli Ding, Chun-Shiang Chung
1Division of Surgical Research, Department of Surgery, Lifespan/Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA.
Background:
Sepsis remains a substantial risk after surgery or other trauma. Macrophage dysfunction, as a component of immune suppression seen during trauma and sepsis, appears to be one of the contributing factors to morbidity and mortality. However, whereas it is known that the ability of macrophages to present antigen and express major histocompatibility complex MHC class II molecules is decreased during sepsis, it is not known to what extent this is associated with the loss of co-stimulatory receptor expression. Our objectives in this study were, therefore, to determine if the expression of co-stimulatory molecules, such as CD40, CD80, or CD86, on peritoneal/splenic/liver macrophages were altered by sepsis (cecal ligation [CL] and puncture [CLP] or necrotic tissue injury (CL) alone; and to establish the contribution of such changes to the response to septic challenge using mice that are deficient in these receptors.
Methods:
To address our first objective, male C3H/HeN mice were subjected to CLP, CL, or sham (n = four to six mice/group), and the adherent macrophages were isolated from the peritoneum, spleen, or liver at 24 h post-insult. The macrophages were then analyzed by flow cytometry for their ex vivo expression of CD40, CD80, CD86, and/or MHC II.
Results:
The expression of CD86 and MHC II, but not CD40 or CD80, were significantly decreased on peritoneal macrophages after the onset of sepsis or CL alone. In addition, CD40 expression was significantly increased in Kupffer cells after sepsis. Alternatively, splenic macrophages from septic or CL mice did not show changes in the expression of CD80, CD86, or CD40. To the degree that the loss of CD86 expression might contribute to the changes reported in macrophage function in septic mice, we subsequently examined the effects of CLP on CD86 -/- mice. Interestingly, we found that, unlike the background controls, neither the serum IL-10 concentrations nor the IL-10 release capacity of peritoneal macrophages from septic CD86 -/- mice were increased.
Conclusion:
Together, these data suggest a potential role for the co-stimulatory receptor CD86/B7-2 beyond that of simply promoting competent antigen presentation to T-cells, but also as a regulator of the anti-inflammatory IL-10 response. Such a role may implicate the latter response in the development of sepsis-induced immune dysfunction.
Insights
Sepsis decreases CD86 and MHC II expression on macrophages, impacting immune response. CD86 deficiency prevents sepsis-induced IL-10 increase, suggesting its role in immune dysfunction.
Area of Science:
- Immunology
- Cell Biology
- Sepsis Research
Background:
- Sepsis and trauma cause immune suppression, partly due to macrophage dysfunction.
- Reduced antigen presentation and MHC class II expression on macrophages are known sepsis effects.
- The role of co-stimulatory receptor expression changes in sepsis-induced immune suppression is unclear.
Purpose of the Study:
- To investigate alterations in CD40, CD80, and CD86 expression on macrophages during sepsis.
- To determine the contribution of altered co-stimulatory receptor expression to sepsis response using knockout mice.
Main Methods:
- Mice underwent cecal ligation and puncture (CLP) or other injury models.
- Peritoneal, splenic, and liver macrophages were isolated 24 hours post-insult.
- Flow cytometry analyzed ex vivo expression of CD40, CD80, CD86, and MHC II.
Main Results:
- Sepsis and injury decreased CD86 and MHC II on peritoneal macrophages but not CD40 or CD80.
- CD40 expression increased on Kupffer cells (liver macrophages) post-sepsis.
- Splenic macrophages showed no significant changes in CD40, CD80, or CD86 expression.
- Septic CD86 knockout mice did not exhibit increased IL-10 serum levels or peritoneal macrophage release.
Conclusions:
- CD86/B7-2 plays a role beyond T-cell antigen presentation, regulating the anti-inflammatory IL-10 response.
- This CD86-mediated IL-10 regulation may contribute to sepsis-induced immune dysfunction.
