Regulated cell death and inflammasome activation in gut injury following traumatic surgery in vitro and in vivo: implication for postoperative death due to multiorgan dysfunction

Lingzhi Wu; Hailin Zhao; Mengxu Zhang; Qizhe Sun; Enqiang Chang; Xinyi Li; Wen Ouyang; Yuan Le; Daqing Ma

doi:10.1038/s41420-023-01647-z

Regulated cell death and inflammasome activation in gut injury following traumatic surgery in vitro and in vivo: implication for postoperative death due to multiorgan dysfunction

Cell Death Discov. 2023 Nov 7;9(1):409. doi: 10.1038/s41420-023-01647-z.

Authors

Lingzhi Wu^#¹, Hailin Zhao^#¹, Mengxu Zhang¹, Qizhe Sun¹, Enqiang Chang¹, Xinyi Li¹, Wen Ouyang^{2

3}, Yuan Le^{4

5}, Daqing Ma^{6

7}

Affiliations

¹ Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
² Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, PR China.
³ Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, PR China.
⁴ Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, PR China. leyuanxy@csu.edu.cn.
⁵ Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, PR China. leyuanxy@csu.edu.cn.
⁶ Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK. d.ma@imperial.ac.uk.
⁷ Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China. d.ma@imperial.ac.uk.

^# Contributed equally.

Abstract

Postoperative multi-organ dysfunction (MOD) is associated with significant mortality and morbidity. Necroptosis has been implicated in different types of solid organ injury; however, the mechanisms linking necroptosis to inflammation require further elucidation. The present study examines the involvement of necroptosis and NLR family pyrin domain containing 3 (NLRP3) inflammasome in small intestine injury following traumatic surgery. Kidney transplantation in rats and renal ischaemia-reperfusion (I/R) in mice were used as traumatic and laparotomic surgery models to study necroptosis and inflammasome activation in the small intestinal post-surgery; additional groups also received receptor-interacting protein kinase 1 (RIPK1) inhibitor necrostatin-1s (Nec-1s). To investigate whether necroptosis regulates inflammasome activity in vitro, necroptosis was induced in human colonic epithelial cancer cells (Caco-2) by a combination of tumour necrosis factor-alpha (TNFα), SMAC mimetic LCL-161 and pan-caspase inhibitor Q-VD-Oph (together, TLQ), and necroptosis was blocked by Nec-1s or mixed lineage kinase-domain like (MLKL) inhibitor necrosulfonamide (NSA). Renal transplantation and renal ischaemia-reperfusion (I/R) upregulated the expression of necroptosis mediators (RIPK1; RIPK3; phosphorylated-MLKL) and inflammasome components (P2X purinoceptor subfamily 7, P2X7R; NLRP3; caspase-1) in the small intestines at 24 h, and Nec-1s suppressed the expression of inflammasome components. TLQ treatment induced NLRP3 inflammasome, promoted cleavage of caspase-1 and interleukin-1 beta (IL-1β), and stimulated extracellular ATP release from Caco-2 cells, and MLKL inhibitor NSA prevented TLQ-induced inflammasome activity and ATP release from Caco-2 cells. Our work suggested that necroptosis and inflammasome interactively promote remote postoperative small intestinal injury, at least in part, through ATP purinergic signalling. Necroptosis-inflammasome axis may be considered as novel therapeutic target for tackling postoperative MOD in the critical care settings.

Abstract

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