Long-term Effects of Severe Sepsis on Dendritic Cell Function.

Dendritic Cells in Sepsis;Epigenetics;Pathology;Health Sciences;Pathology

Wen, HaitaoPhan, Sem H. ;

University of Michigan

关键词: Dendritic Cells in Sepsis;    Epigenetics;    Pathology;    Health Sciences;    Pathology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/57685/haiwen_1.pdf?sequence=2&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Sepsis is often described as an initial overwhelming systemic immune response, followed by a compensatory anti-inflammatory response.Using an experimental model of severe sepsis induced by cecal ligation and puncture (CLP), we identified the chemokine receptor CCR6 as a key component of acute sepsis.Naïve CCR6-deficient (CCR6-/-) mice possessed lower numbers of macrophages and dendritic cells (DCs), but a higher number of B cells in the peritoneal cavity, as compared to controls.Peritoneal macrophages isolated from CCR6-/- generated lower levels of pro-inflammatory cytokines following LPS challenge, which may serve as a protective mechanism against the lethal effects of sepsis.DC recruitment into the peritoneal cavity was impaired in CCR6-/- mice during the evolution of CLP-induced peritonitis.Clinical studies indicate that patients surviving severe sepsis are immunosuppressed, which is dictated by ill-understood mechanisms.We have modeled this response and have studied DCs recovered from animals surviving severe peritonitis.Although tissue DCs were initially depleted in septic animals, they subsequently returned to pre-septic levels.However, the repopulated DCs demonstrated a long-term reduction in DC-derived IL-12 expression and impaired antigen-presenting function.Using chromatin immunoprecipitation (ChIP) techniques, we demonstrated that the deficiency in DC-derived IL-12 was related to stable reciprocal changes in histone H3 lysine-4 trimethylation (H3K4me3) and H3K27me2, due to changes in cognate histone methyltransferase (HMT) complexes on the Il12p35 and Il12p40 promoters.Furthermore, stefin A1, an inhibitor of a cysteine protease (cathepsin S) necessary for antigen processing, was dramatically upregulated in post-septic spleen and lung DCs.In order to investigate the immune status after severe sepsis, we challenged survivors of severe sepsis with lung granuloma-inducing Schistosoma mansoni eggs.This granulomatous response is a well-studied cell-mediated immune reaction, which is characterized by elevated levels of type-2 cytokines.Pulmonary granulomas induced by S. mansoni eggs in CLP survivors were significantly larger, contained more eosinophils, and lower IL-12 and higher Th2 cytokines than in sham mice.Collectively, these studies demonstrate an important role of CCR6 in the acute phase of severe sepsis and reveal an epigenetic mechanism responsible for the downregulation of interleukin-12, which may explain long-term immunosuppression associated with severe sepsis.