Abstract
Sepsis is a syndrome characterized by life-threatening organ dysfunction caused by the dysregulated host response to an infection. Sepsis, especially septic shock and multiple organ dysfunction is a medical emergency associated with high morbidity, high mortality, and prolonged after-effects. Over the past 20 years, regulatory T cells (Tregs) have been a key topic of focus in all stages of sepsis research. Tregs play a controversial role in sepsis based on their heterogeneous characteristics, complex organ/tissue-specific patterns in the host, the multi-dimensional heterogeneous syndrome of sepsis, the different types of pathogenic microbiology, and even different types of laboratory research models and clinical research methods. In the context of sepsis, Tregs may be considered both angels and demons. We propose that the symptoms and signs of sepsis can be attenuated by regulating Tregs. This review summarizes the controversial roles and Treg checkpoints in sepsis.
Highlights
A study of the global burden of disease from 1990 to 2017 showed that an estimated 48.9 million (38.9-62.9) sepsis cases were recorded globally and 11.0 million (10.1-12.0) sepsis-related deaths were reported in 2017, representing 19.7% (18.2-21.4) of global deaths [1]
The first three days of sepsis are defined as the early stage; in these cases, more than 80% of patients first seek emergency medicine according to their clinical manifestations of the biological systemic immune-inflammatory response [26, 36,37,38,39,40,41,42,43]
Splenectomy improved 28- day survival in a secondary sepsis cecal ligation perforation (CLP) mouse model from 62% to 92%, which was concurrent with the lower release of inflammatory cytokines (IL6, CXCL-1, and MCP-1) and a 41% increase in Tregs within 48 hours [65]
Summary
A study of the global burden of disease from 1990 to 2017 showed that an estimated 48.9 million (38.9-62.9) sepsis cases were recorded globally and 11.0 million (10.1-12.0) sepsis-related deaths were reported in 2017, representing 19.7% (18.2-21.4) of global deaths [1]. In a clinically relevant cecal slurry (CS) induced model of recurrent sepsis, increased T cell exhaustion and poor prognosis (including reduced survival rate and body weight) was observed in aged (18-24 months old) compared with young (5 week old) female or male C57BL6/J mice Their symptoms persisted for over 50 days and were associated with increased PD-1 expression on Tregs [59]. Since the absolute number of Foxp3+ Tregs in the lung tissues of CLP-induced septic mice increased nearly two-fold on the third day and returned to normal levels on the seventh day, mice were susceptible to intratracheal injection of Pseudomonas aeruginosa for 3 days, but not for 7 days [90] This suggests that Tregs have different functions at different stages of sepsis and contribute to secondary P. aeruginosa infection. These results are contradictory, they do imply that Foxp3+ Tregs play an important role in amending early, late, and even long-term immune disturbances after sepsis
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