• Huachen Wang, Meixiang Wang, Junlan Chen, Hongda Hou, Zheng Guo, Hong Yang, Hua Tang, and Bing Chen.
• Institute of Infectious Diseases, The Second Hospital of Tianjin Medical University, 23 Pingjiang Road, Tianjin, 300211, People's Republic of China.
• Crit Care. 2023 Dec 13; 27 (1): 490490.

BackgroundSepsis is defined as a life-threatening syndrome caused by an unbalanced host response to infection. The role of interleukin (IL)-36 cytokines binding to the IL-36 receptor (IL-36R) in host response during sepsis remains unknown.MethodsSerum IL-36 level was measured in 47 septic patients sampled on the day of intensive care unit (ICU) and emergency department admission, 21 non-septic ICU patient controls, and 21 healthy volunteers. In addition, the effects of IL-36R deletion on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis was determined.ResultsOn the day of ICU and emergency department admission, the patients with sepsis showed a significant increase in serum IL-36 levels compared with ICU patient controls and healthy volunteers, and the serum IL-36 levels were related to the severity of sepsis. Non-survivors of septic patients displayed significantly lower serum IL-36 levels compared with survivors. A high serum IL-36 level in ICU and emergency department admission was associated with 28-day mortality, and IL-36 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, IL-36R deletion increased lethality in CLP-induced polymicrobial sepsis. Septic mice with IL-36R deletion had higher bacterial load and demonstrated more severe multiple organ injury (including lung, liver, and kidney) as indicated by clinical chemistry and histopathology. Mechanistically, IL-36R ligands released upon lung damage activated IL-36R+lung fibroblasts thereby inducing expression of the antimicrobial protein lipocalin 2. Moreover, they induced the apoptosis of lung epithelial cells.ConclusionsSeptic patients had elevated serum IL-36 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-36R deletion in increasing lethality.© 2023. The Author(s).

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