Examination of the role of necroptotic damage-associated molecular patterns in tissue fibrosis

Abstract

Fibrosis is defined as the abnormal and excessive deposition of extracellular matrix (ECM) components, which leads to tissue or organ dysfunction and failure. However, the pathological mechanisms underlying fibrosis remain unclear. The inflammatory response induced by tissue injury is closely associated with tissue fibrosis. Recently, an increasing number of studies have linked necroptosis to inflammation and fibrosis. Necroptosis is a type of preprogrammed death caused by death receptors, interferons, Toll-like receptors, intracellular RNA and DNA sensors, and other mediators. These activate receptor-interacting protein kinase (RIPK) 1, which recruits and phosphorylates RIPK3. RIPK3 then phosphorylates a mixed lineage kinase domain-like protein and causes its oligomerization, leading to rapid plasma membrane permeabilization, the release of cellular contents, and exposure of damage-associated molecular patterns (DAMPs). DAMPs, as inflammatory mediators, are involved in the loss of balance between extensive inflammation and tissue regeneration, leading to remodeling, the hallmark of fibrosis. In this review, we discuss the role of necroptotic DAMPs in tissue fibrosis and highlight the inflammatory responses induced by DAMPs in tissue ECM remodeling. By summarizing the existing literature on this topic, we underscore the gaps in the current research, providing a framework for future investigations into the relationship among necroptosis, DAMPs, and fibrosis, as well as a reference for later transformation into clinical treatment.

Identification of TNFRSF1A as a potential biomarker for osteosarcoma

“…Immune infiltration and immune checkpoint analyses performed on the three datasets indicated that TNFRSF1A is a good diagnostic marker of OS. Necroptosis is preprogrammed death triggered by death receptors, interferons, toll-like receptors, intracellular RNA and DNA sensors, and other mediators [42]. Based on univariate Cox regression analysis, among the 14 evaluated NRGs [22], the prioritization of TN-FRSF1A arises from its noteworthy association with OS prognosis and its pertinence in immune-related mechanisms in OS pathogenesis.…”

Role of the epithelial barrier in intestinal fibrosis associated with inflammatory bowel disease: relevance of the epithelial-to mesenchymal transition

“…Epithelial cell injury and death are common events in inflammatory diseases, such us UC and CD, but they have been only recently recognized as drivers of fibrosis. For instance, an increasing number of studies have linked necroptosis (a form of programmed necrosis) to inflammation and fibrosis in renal, liver, heart or lung fibrosis ( Liu et al, 2022 ). Cell products released by cells undergoing necrosis (passive, programmed, or after apoptosis) are called damage-associated molecular patterns (DAMPs), that can directly activate profibrotic responses of immune cells or nonimmune cells (epithelial cells, endothelial cells, and fibroblasts) triggering fibrosis ( Liu et al, 2022 ).…”

“…For instance, an increasing number of studies have linked necroptosis (a form of programmed necrosis) to inflammation and fibrosis in renal, liver, heart or lung fibrosis ( Liu et al, 2022 ). Cell products released by cells undergoing necrosis (passive, programmed, or after apoptosis) are called damage-associated molecular patterns (DAMPs), that can directly activate profibrotic responses of immune cells or nonimmune cells (epithelial cells, endothelial cells, and fibroblasts) triggering fibrosis ( Liu et al, 2022 ). In addition, epithelial cells contain a myriad of intracellular substances normally not recognized by the immune system but, during cell necrosis, they are passively released in the surrounding microenvironment and trigger inflammation.…”

“…IBD tissue releases calprotectin (S100A12, S100A8/S100A9 complexes) and HMGB1 which serve as faecal biomarkers of intestinal inflammation ( Nanini et al, 2018 ). The role of several necroptotic DAMPs and their receptors have been described in the main fibrotic diseases, except in intestinal fibrosis associated to IBD ( Liu et al, 2022 ), where further studies are needed. In this line, Scarpa and collaborators have reported that epithelial cell-derived DAMPS (IL1α) elicit a potent proinflammatory cytokine response from human intestinal fibroblasts.…”