PMID- 38093296 OWN - NLM STAT- MEDLINE DCOM- 20231220 LR - 20240405 IS - 1466-609X (Electronic) IS - 1364-8535 (Print) IS - 1364-8535 (Linking) VI - 27 IP - 1 DP - 2023 Dec 13 TI - Interleukin-36 is overexpressed in human sepsis and IL-36 receptor deletion aggravates lung injury and mortality through epithelial cells and fibroblasts in experimental murine sepsis. PG - 490 LID - 10.1186/s13054-023-04777-z [doi] LID - 490 AB - BACKGROUND: Sepsis 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. METHODS: Serum 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. RESULTS: On 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. CONCLUSIONS: Septic 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. CI - (c) 2023. The Author(s). FAU - Wang, Huachen AU - Wang H AD - Institute of Infectious Diseases, The Second Hospital of Tianjin Medical University, 23 Pingjiang Road, Tianjin, 300211, People's Republic of China. AD - Intensive Care Unit, The Second Hospital of Tianjin Medical University, Tianjin, China. FAU - Wang, Meixiang AU - Wang M AD - The First Affiliated Hospital of Shandong First Medical University, Jinan, China. FAU - Chen, Junlan AU - Chen J AD - State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China. FAU - Hou, Hongda AU - Hou H AD - Institute of Infectious Diseases, The Second Hospital of Tianjin Medical University, 23 Pingjiang Road, Tianjin, 300211, People's Republic of China. AD - Intensive Care Unit, The Second Hospital of Tianjin Medical University, Tianjin, China. FAU - Guo, Zheng AU - Guo Z AD - Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Ave, Nashville, TN, USA. FAU - Yang, Hong AU - Yang H AD - Intensive Care Unit, The Second Hospital of Tianjin Medical University, Tianjin, China. AD - The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, China. FAU - Tang, Hua AU - Tang H AD - Department of Rheumatology and Autoimmunology, Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, 250014, Shandong, China. FPXusmile103@163.com. AD - Institute of Infection and Immunity, Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250000, Shandong, China. FPXusmile103@163.com. FAU - Chen, Bing AU - Chen B AD - Institute of Infectious Diseases, The Second Hospital of Tianjin Medical University, 23 Pingjiang Road, Tianjin, 300211, People's Republic of China. cb20202023@163.com. AD - Intensive Care Unit, The Second Hospital of Tianjin Medical University, Tianjin, China. cb20202023@163.com. LA - eng PT - Journal Article DEP - 20231213 PL - England TA - Crit Care JT - Critical care (London, England) JID - 9801902 RN - 0 (Interleukins) SB - IM MH - Animals MH - Humans MH - Mice MH - Disease Models, Animal MH - Epithelial Cells MH - Fibroblasts MH - Interleukins MH - *Lung Injury MH - *Sepsis PMC - PMC10717293 OTO - NOTNLM OT - IL-36 OT - IL-36R OT - Inflammation OT - Mortality OT - Sepsis COIS- The authors declare that they have no competing interests. EDAT- 2023/12/14 06:41 MHDA- 2023/12/17 16:21 PMCR- 2023/12/13 CRDT- 2023/12/14 00:04 PHST- 2023/09/06 00:00 [received] PHST- 2023/12/11 00:00 [accepted] PHST- 2023/12/17 16:21 [medline] PHST- 2023/12/14 06:41 [pubmed] PHST- 2023/12/14 00:04 [entrez] PHST- 2023/12/13 00:00 [pmc-release] AID - 10.1186/s13054-023-04777-z [pii] AID - 4777 [pii] AID - 10.1186/s13054-023-04777-z [doi] PST - epublish SO - Crit Care. 2023 Dec 13;27(1):490. doi: 10.1186/s13054-023-04777-z.