Abstract
Endotoxin tolerance (ET) is suggested to attenuate the severity of acute liver failure (ALF) in mice, possibly through both innate and adaptive immunity. However, the involvement of regulatory dendritic cells (DCregs) in ET has not been fully elucidated. In this study, their effect on ALF in mice was investigated. Splenic DCregs from ET-exposed mice (ET-DCregs) showed lower expression levels of CD40, CD80, and MHC-II markers and stronger inhibition of allogenic T cells and regulation of IL-10 and IL-12 secretion than splenic DCregs from normal mice (nDCregs). Moreover, the mRNA and protein levels of TNF-α and P65 in splenic ET-DCregs were significantly lower than those in the splenic nDCregs. The survival rate was significantly increased and liver injury was mitigated in mice with ALF treated with splenic ET-DCregs. In addition, A20 expression was decreased in the liver of ALF mice, but elevated after infusion of splenic nDCregs and ET-DCregs, and a much higher elevation was observed after infusing the latter cells. The functionality of splenic DCregs was altered after ET exposure, contributing to protection of the livers against D-GalN/LPS-induced ALF.
Highlights
DCs can be classified into different subsets in line with their functions and/or developmental stages
The expression of costimulatory molecules CD40, CD80, and MHC-II was further examined on MACS-sorted CD11ClowCD45RBhigh DCs
When CD11ClowCD45RBhigh DCs were co-cultured with CD4+T cells at various ratios, including 1:10, 1:50, and 1:100, for 24 hours, as shown Table 1, reduced CD4+T-cell proliferation was observed with CD11ClowCD45RBhigh DCs from LPS-treated mice, and the culture medium from the same CD11ClowCD45RBhigh DCs contained a higher concentration of IL-10 and lower concentration of IL-12, indicating a tilled differentiation to Th1 cells, compared to that from CD11ClowCD45RBhigh DCs from normal mice
Summary
DCs can be classified into different subsets in line with their functions and/or developmental stages. The splenic DC class contains heterogeneous subsets of DCs with a spectrum of functions and morphologies[8]. CD11ClowCD45RBhigh DCs, a subtype of DCregs with low expression of CD11c and high expression of CD45RB, can respond to an inflammatory stimulus[9]. Recent studies suggested that splenic DCregs inhibit inflammation by generating anergic T cells and regulatory T cells (Tregs), as well as deleting peripheral T cells under lethal conditions of endotoxemia and bacterial peritonitis[10]. In the current study, we examined the effect of splenic DCs derived from LPS-pretreated mice on D-GalN/LPS–induced acute liver failure and explored the possible mechanisms underlying ET
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