Oxidative stress, DAMPs, and immune cells in acute pancreatitis: molecular mechanisms and therapeutic prospects

Abstract

Acute pancreatitis (AP) is a gastrointestinal disease characterized by inflammation of the pancreas and is associated with high rates of morbidity and mortality. The pathogenesis of AP involves a complex interplay of cellular and molecular mechanisms, including oxidative stress, damage-associated molecular patterns (DAMPs), and the infiltration of various immune cells. This review aims to provide a comprehensive overview of the molecular mechanisms underlying AP, the role of different immune cells in its progression and potential therapeutic perspectives. Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) and the antioxidant defense system, plays a crucial role in AP. ROS not only contribute to cell necrosis and apoptosis, but also activate immune cells and perpetuate inflammation. DAMPs released from damaged cells activate the innate immune response by interacting with pattern recognition receptors (PRRs), leading to the recruitment of immune cells such as neutrophils, macrophages and dendritic cells. These immune cells further amplify the inflammatory response by releasing cytokines and chemokines. Neutrophils are among the first responders in AP, contributing to both tissue damage and repair, as well as the double-site sword effect of neutrophil extracellular traps (NETs). Other immune cells, including T cells, dendritic cells, mast cells and monocytes/macrophages, are involved in modulating the inflammatory response and tissue repair processes. The balance between pro- and anti-inflammatory immune responses is critical in determining the severity and outcome of AP. A table of targeted drugs or substances available in clinical trials is provided at the end of this paper, with the aim of providing available opportunities for clinical treatment. Nevertheless, precise targeted drugs are still urgently needed in clinical treatment, where more in-depth research is needed.

Keywords: DAMPs; acute pancreatitis; macrophage; neutrophil; oxidative stress.

Figure 1

In acute pancreatitis, the abnormal activation of pancreatic enzymes leads to calcium overload within pancreatic cells, resulting in an increase in intracellular ROS. This also causes damage to acinar cells. Then, damage to pancreatic cells leads to the release of damage-associated molecular patterns (DAMPs, such as HMGB1, ATP, and mitochondrial DNA) into the extracellular space. These DAMPs are recognized by pattern recognition receptors (TLRs2/4) of macrophages and dendritic cells, activating NK-κB pathway and then NLRP3 inflammasome, to release IL-1β and other cytokines or chemokines. This further results in more immune cells recruiting to the site of injury, amplifying the inflammatory response and causing tissue damage. ROS can also be generated through the respiratory burst of neutrophils. ROS can promote the polarization of macrophages towards the M1 phenotype and the differentiation of T cells towards the Th1/Th17 direction. DAMPs, Damage-Associated Molecular Patterns; HMGB1, High Mobility Group Box 1; IL, Interleukin; MyD-88, Myeloid Differentiation Primary Response 88; NLRP3, NLR Family Pyrin Domain Containing 3; RAGE, Receptor for Advanced Glycation Endproducts; ROS, Reactive Oxygen Species; Th, T Helper Cell; TLR, Toll-Like Receptor.

Figure 2

The classic pathway of NET formation in acute pancreatitis. Stimulus, such as LPS and platelets, trigger the MEK-pathway or PKC, resulting in the activation of NOX to provoke the production of ROS. ROS enter the azurophilic granule to liberate NE from the protein complex composed of MPO and NE. NE is transferred into the nucleus, subsequent to which core histones undergo proteolytic cleavage, culminating in chromatin depolymerization. Calcium ionophores cause a high concentration of Ca²⁺, which activate PAD4 to catalyze histone citrolination, destroy histone binding to DNA, and promote chromatin depolymerization. Decondensed chromatin DNA, histones, and cytosolic granzymes mix up, through the pore punched by GSDMD, they are effluxed to the extracellular space, and finally form NETs. Ca²⁺, Calcium ion; DNA, Deoxyribonucleic acid; ER, Endoplasmic reticulum; GSDMD, Gasdermin D; IL-8, interleukin 8;LPS, Lipopolysaccharide; MPO, Myeloperoxidase; NET, Neutrophil extracellular trap; NE, Neutrophil elastase; NOX, Nicotinamide adenine dinucleotide phosphate oxidase; PAD4, Protein arginine deiminase 4; PKC, Protein kinase C; ROS, Reactive oxygen species; TLR, Toll-like receptor.

Figure 3

(a) Dendritic cells recognize CCL17 via CCR4 and activate T cells through downstream signaling pathways, while also secreting IL-33 in response to DAMPs stimulation. (b) In Treg or Th22 cells, the AhR signaling pathway is activated, leading to the secretion of IL-10 and IL-22, which regulate T cell differentiation. (c) Mast cells receive IL-33 signaling and undergo degranulation. AhR, Aryl hydrocarbon receptor; ARNT, Aryl hydrocarbon receptor nuclear translocator; CCL17, Chemokine (C-C motif) ligand 17; CCR4, C-C chemokine receptor type 4; CD80, Cluster of differentiation 80; CYP1A1, Cytochrome P450 family 1 subfamily A member 1; CYP1B1, Cytochrome P450 family 1 subfamily B member 1; ER, Endoplasmic reticulum; GPCR, G protein-coupled receptor; MHC, Major histocompatibility complex; ST2, Suppression of tumorigenicity 2 (IL-33 receptor).

Figure 4

The polarization of M0 macrophage. The upper part of the figure is the path with a polarization of M1, and the bottom half is a path with a polarization of M2. AP-1, activator protein 1; c-Fos, cellular Fos; IKK, IκB kinase; JAK, janus kinase; MAPK, mitogen-activated protein kinase; MIF, macrophage migration inhibitory factor; MyD88, myeloid differentiation primary response 88; NEMO, NF-κB essential modulator; Rel A, v-rel avian reticuloendotheliosis viral oncogene homolog A (also known as p65); STAT6, signal transducer and activator of transcription 6; TRAF, TNF receptor-associated factor; Ym1, chitinase-like protein 3.