BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction

作者：Nicholas J. Shubin, Chun S. Chung, Daithi S. Heffernan, Lydea R. Irwin, Sean F. Monaghan, Alfred Ayala · 发表于：Journal of Leukocyte Biology · 年份：2012 · DOI：10.1189/jlb.1211641 · 被引用次数：94 · 研究领域：Sepsis Diagnosis and Treatment、Immune Response and Inflammation、Immune cells in cancer

A proper innate inflammatory response is essential for prevention of the systemic inflammation associated with sepsis. BTLA is an immune-regulatory receptor demonstrated to be expressed not only on adaptive immune populations and have potent inhibitory effects on CD4(+) T cells but is also expressed on innate cell populations (CD11c(+) and CD11b(+) cells) and has been shown to diminish pathogen clearance following bacterial and parasite infection. The role of BTLA in sepsis and the mechanisms by which BTLA alters pathogen clearance, however, have not been addressed clearly. Here, we show that following acute experimental sepsis induction in mice (CLP), the number of infiltrating BTLA- and HVEM (the ligand for BTLA)-expressing macrophages, inflammatory monocytes, mature and immature DCs, and neutrophils increased in the peritoneum compared with sham surgery, suggesting that a high level of HVEM:BTLA interactions occurs between these cells at the site of septic insult. Given this, we evaluated BTLA(-/-) mice, 24 h post-CLP, and observed a marked increase in the degree of activation on these cell populations, as well as a reduction in peritoneal bacterial burden and IL-10 induction, and most importantly, BTLA(-/-) mice exhibited a higher rate of survival and protection from organ injury when compared with WT mice. Such changes were not restricted to experimental mice, as circulating BTLA+ and HVEM+ monocytes and HVEM+ granulocytes were increased in septic ICU patients, supportin...