Digestive Inflammation: Role of Proteolytic Dysregulation

Abstract

Dysregulation of the proteolytic balance is often associated with diseases. Serine proteases and matrix metalloproteases are involved in a multitude of biological processes and notably in the inflammatory response. Within the framework of digestive inflammation, several studies have stressed the role of serine proteases and matrix metalloproteases (MMPs) as key actors in its pathogenesis and pointed to the unbalance between these proteases and their respective inhibitors. Substantial efforts have been made in developing new inhibitors, some of which have reached clinical trial phases, notwithstanding that unwanted side effects remain a major issue. However, studies on the proteolytic imbalance and inhibitors conception are directed toward host serine/MMPs proteases revealing a hitherto overlooked factor, the potential contribution of their bacterial counterpart. In this review, we highlight the role of proteolytic imbalance in human digestive inflammation focusing on serine proteases and MMPs and their respective inhibitors considering both host and bacterial origin.

Keywords: digestive inflammation; gut microbiota; holobiont; protease; serpin.

Figure 1

Schematic representation of matrix metalloproteases (MMPs) mechanisms of action in healthy contet (Normal) and in inflammatory bowel disease (IBD) pathophysiogenesis. The release of soluble TNF-α resulting from the shedding of membrane-bound TNF by MMPs causes mucus depletion (1) and tight-junction destabilization (2), leading to increased epithelial permeability and bacterial translocation. The abrogation of myofibroblast ability in suppressing Th1/Th17 occurs after the MMP processing of membrane-bound PD-L1 to produce soluble PD-L1 (3). Cytokine processing contributes to inflammation processes (4). PGP generation through collagen degradation by MMPs induces neutrophil transmigration and stimulates neutrophil MMP and CXCL8 secretion, therefore sustaining the inflammatory context (5). CXCL8: (C-X-C motif) ligand 8, MLCK: myosin light-chain kinase, PD-L1: programmed death-ligand 1, mPD-L1: membrane-bound PD-L1, sPD-L1: soluble PD-L1, (N-Ac)-PGP: (N-acetyl)-proline-glycine-proline, TJ: tight junction, TNF: tumor necrosis factor α.

Figure 2

Schematic illustration of the serine protease mode of action in healthy context (Normal) and in inflammatory bowel disease (IBD) pathology. Epithelial barrier impairment is associated with serine protease action on the tight junction through direct cleavage. (1) Indirect destabilization deriving from protease-activated receptor (PAR) activation (2), mucus degradation (3) and cytokine processing (4). MLC: myosin light-chain, P-MLC: phosphorylated MLC, MLCK: myosin light-chain kinase, PAR: protease-activated receptor, TJ: tight junction.