Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice.

Sunil S Karhadkar,Alexander M Fagenson,Fatma Saaoud,Gayani Nanayakkara,Hong Wang,Antonio Di Carlo,Keman Xu,Kwan N Lau,Nirag C Jhala,Yu Sun,Charles Drummer,Xiaofeng Yang,Lu Liu,Xiaohua Jiang

doi:10.3390/pathogens9110879

Sunil S Karhadkar, Alexander M Fagenson + Show 12 more

Open Access

https://doi.org/10.3390/pathogens9110879

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Abstract

Ischemia reperfusion injury (IRI) during liver transplantation increases morbidity and contributes to allograft dysfunction. There are no therapeutic strategies to mitigate IRI. We examined a novel hypothesis: caspase 1 and caspase 11 serve as danger-associated molecular pattern (DAMPs) sensors in IRI. By performing microarray analysis and using caspase 1/caspase 11 double-knockout (Casp DKO) mice, we show that the canonical and non-canonical inflammasome regulators are upregulated in mouse liver IRI. Ischemic pre (IPC)- and post-conditioning (IPO) induce upregulation of the canonical and non-canonical inflammasome regulators. Trained immunity (TI) regulators are upregulated in IPC and IPO. Furthermore, caspase 1 is activated during liver IRI, and Casp DKO attenuates liver IRI. Casp DKO maintained normal liver histology via decreased DNA damage. Finally, the decreased TUNEL assay-detected DNA damage is the underlying histopathological and molecular mechanisms of attenuated liver pyroptosis and IRI. In summary, liver IRI induces the upregulation of canonical and non-canonical inflammasomes and TI enzyme pathways. Casp DKO attenuate liver IRI. Development of novel therapeutics targeting caspase 1/caspase 11 and TI may help mitigate injury secondary to IRI. Our findings have provided novel insights on the roles of caspase 1, caspase 11, and inflammasome in sensing IRI derived DAMPs and TI-promoted IRI-induced liver injury.

Highlights

Ischemia reperfusion injury (IRI) is an unavoidable consequence during organ transplantation, hemorrhagic shock [1]/cardiogenic shock [2], myocardial infarction [3], and acute limb ischemia [4].IRI following liver transplantation contributes to postoperative organ dysfunction, and increases the risk of acute and chronic rejection with subsequent graft failure [5]
The canonical inflammasome and caspase 1 pathway play a critical role in sensing liver IRI-derived
Non-canonical inflammasome and caspase 4/caspase 11 are responsible for the formation of protein channel/pores on the plasma membrane to release mature IL-1β and IL-18 and pyroptosis [56] (Figure 1B)

Summary

Introduction

Ischemia reperfusion injury (IRI) is an unavoidable consequence during organ transplantation, hemorrhagic shock [1]/cardiogenic shock [2], myocardial infarction [3], and acute limb ischemia [4]. IRI following liver transplantation contributes to postoperative organ dysfunction, and increases the risk of acute and chronic rejection with subsequent graft failure [5]. Allograft injury occurs during the cold ischemic [6] and warm [7] reperfusion phases. Activation of TLR4 on macrophages [17] triggers a cascade leading to inflammation and apoptosis/pyroptosis (inflammatory cell death) [18,19,20,21,22]. Liver sinusoidal endothelial cells are the first to become injured secondary to a microcirculatory disturbance that starts during the cold ischemic phase of organ preservation [6]

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