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.
