Abstract
IntroductionLymphocyte apoptosis and monocyte dysfunction play a pivotal role in sepsis-induced immunosuppression. Programmed death-1 (PD1) and its ligand programmed death ligand-1 (PD-L1) exert inhibitory function by regulating the balance among T cell activation, tolerance, and immunopathology. PD-1 deficiency or blockade has been shown to improve survival in murine sepsis. However, PD-L1 and PD-1 differ in their expression patterns and the role of PD-L1 in sepsis-induced immunosuppression is still unknown.MethodsSepsis was induced in adult C57BL/6 male mice via cecal ligation and puncture (CLP). The expression of PD-1 and PD-L1 expression on peripheral T cells, B cells and monocytes were measured 24 hours after CLP or sham surgery. Additionally, the effects of anti-PD-L1 antibody on lymphocyte number, apoptosis of spleen and thymus, activities of caspase-8 and caspase-9, cytokine production, bacterial clearance, and survival were determined.ResultsExpression of PD-1 on T cells, B cells and monocytes and PD-L1 on B cells and monocytes were up-regulated in septic animals compared to sham-operated controls. PD-L1 blockade significantly improved survival of CLP mice. Anti-PD-L1 antibody administration prevented sepsis-induced depletion of lymphocytes, increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production, decreased IL-10 production, and enhanced bacterial clearance.ConclusionsPD-L1 blockade exerts a protective effect on sepsis at least partly by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Anti-PD-L1 antibody administration may be a promising therapeutic strategy for sepsis-induced immunosuppression.
Highlights
Lymphocyte apoptosis and monocyte dysfunction play a pivotal role in sepsis-induced immunosuppression
Expression of Programmed death-1 (PD-1) on T cells, B cells and monocytes and programmed death ligand-1 (PD-L1) on B cells and monocytes were upregulated in septic animals compared to sham-operated controls
PD-L1 blockade exerts a protective effect on sepsis at least partly by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction
Summary
Lymphocyte apoptosis and monocyte dysfunction play a pivotal role in sepsis-induced immunosuppression. PD-L1 and PD-1 differ in their expression patterns and the role of PD-L1 in sepsis-induced immunosuppression is still unknown. Accumulating evidence [5,6,7] suggests the pivotal role of apoptosis in sepsis-induced immunosuppression. In multiple animal models of sepsis, survival rates have been remarkably improved by inhibiting lymphocyte apoptosis by using selective caspase inhibitors [11,12]; altering proapoptotic/antiapoptotic protein expression [13,14]; treatment with survival promoting cytokines such as interleukin (IL)-7 [15] and/or IL-15 [16]; and modulating costimulatory receptors [17,18]
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