Endoplasmic reticulum stress in acute pancreatitis: Exploring the molecular mechanisms and therapeutic targets

Abstract

Acute pancreatitis (AP) is associated with multiple cellular mechanisms that trigger and or are triggered by the inflammatory injury and death of the acinar cells. One of the key mechanisms is the endoplasmic reticulum (ER) stress, which manifests as an accumulation of misfolded proteins within ER, an event that has proinflammatory and proapoptotic consequences. Hence, the degree of cell insult during AP could considerably depend on the signaling pathways that are upregulated during ER stress and its resulting dyshomeostasis such as C/EBP homologous protein (CHOP), cJUN NH2-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and NOD-like receptor protein 3 (NLRP3) inflammasome. Exploring these molecular pathways is an interesting area for translational medicine as it may lead to identifying new therapeutic targets in AP. This review of the literature aims to shed light on the different roles of ER stress in the etiopathogenesis and pathogenesis of AP. Then, it specifically focuses on the therapeutic implications of ER stress in this context.

Keywords: Acute pancreatitis; CHOP; Endoplasmic reticulum stress; NF-κB; Pyroptosis; UPR.

Fig. 1

Consequences of endoplasmic reticulum (ER) stress on acinar cells during acute pancreatitis. The accumulation of misfolded proteins and activation of ER stress pathways within acinar cells results in the initiation of multiple cytoplasmic and nuclear processes: (i) autophagy: which occurs in response to JNK activation and mTOR inhibition; (ii) cell death: five types of programmed and nonprogrammed cell death mechanisms can develop through ER stress including apoptosis, pyroptosis, necroptosis, ferroptosis (iron homeostasis-dependent death), and necrosis; (iii) inflammation: ER stress and unfolded proteins response trigger the activation of NFκB via ER overload response. Ultimately, NFκB acts by inducing the transcriptional expression of NOD-like receptor protein 3, which, in turn, induces caspase-mediated activation of pro-IL-1β and pro-IL-18. Once activated, these cytokines stimulate the recruitment and proliferation of inflammatory cells, thus, favoring cell insults. Abbreviations used: JNK, cJUN NH2-terminal kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor protein 3.

Fig. 2

Main current drugs showing potential activity on endoplasmic reticulum stress in acute pancreatitis models.