Toll-Like Receptors 2 and 4 Contribute to Sepsis-Induced Depletion of Spleen Dendritic Cells

作者：Pene Frederic; Courtine Emilie; Ouaaz Fatah; Zuber Benjamin; Sauneuf Bertrand; Sirgo Gonzalo; Rousseau Christophe; Toubiana Julie; Balloy Viviane; Chignard Michel; Mira Jean Paul; Chiche Jean Daniel^*

来源：Infection and Immunity, 2009, 77(12): 5651-5658.

DOI：10.1128/IAI.00238-09

Depletion of dendritic cells (DC) in secondary lymphoid organs is a hallmark of sepsis-induced immune dysfunction. In this setting, we investigated if Toll-like receptor (TLR)-dependent signaling might modulate the maturation process and the survival of DC. Using a model of sublethal polymicrobial sepsis induced by cecal ligation and puncture, we investigated the quantitative and functional features of spleen DC in wild-type, TLR2(-/-), TLR4(-/-), and TLR2(-/-) TLR4(-/-) mice. By 24 h, a decrease in the relative percentage of CD11c(high) spleen DC occurred in wild-type mice but was prevented in TLR2(-/-), TLR4(-/-), and TLR2(-/-) TLR4(-/-) mice. In wild-type mice, sepsis dramatically affected both CD11c(+) CD8 alpha(+) and CD11c(+) CD8 alpha(-) subsets. In all three types of knockout mice studied, the CD11c(+) CD8 alpha(+) subset followed a depletion pattern similar to that for wild-type mice. In contrast, the loss of CD11c(+) CD8 alpha(-) cells was attenuated in TLR2(-/-) and TLR4(-/-) mice and completely prevented in TLR2(-/-) TLR4(-/-) mice. Accordingly, apoptosis of spleen DC was increased in septic wild-type mice and inhibited in knockout mice. In addition we characterized the functional features of spleen DC obtained from septic mice. As shown by increased expression of major histocompatibility complex class II and CD86, polymicrobial sepsis induced maturation of DC, with subsequent increased capacity to prime T lymphocytes, similarly in wild-type and knockout mice. In response to CpG DNA stimulation, production of interleukin-12 was equally impaired in DC obtained from wild-type and knockout septic mice. In conclusion, although dispensable for the DC maturation process, TLR2 and TLR4 are involved in the mechanisms leading to depletion of spleen DC following polymicrobial sepsis.

• 出版日期2009-12