Inflammasome biology in fibrogenesis

Abstract

Pathogens and sterile insults both result in an inflammatory response. A significant part of this response is mediated by cytosolic machinery termed as the inflammasome which results in the activation and secretion of the cytokines interleukin-1β (IL-1β) and IL-18. Both of these are known to result in the activation of an acute inflammatory response, resulting in the production of downstream inflammatory cytokines such as tumor necrosis factor (TNF-α), interferon-gamma (IFN-γ), chemotaxis of immune cells, and induction of tissue injury. Surprisingly this very acute inflammatory pathway is also vital for the development of a full fibrogenic response in a number of organs including the lung, liver, and skin. There is evidence for the inflammasome having a direct role on tissue specific matrix producing cells such as the liver stellate cell, and also indirectly through the activation of resident tissue macrophage populations. The inflammasome requires stimulation of two pathways for full activation, and initiating stimuli include Toll-like receptor (TLR) agonists, adenosine triphosphate (ATP), particulates, and oxidative stress. Such a role for an acute inflammatory pathway in fibrosis runs counter to the prevailing association of TGF-β driven anti-inflammatory and pro-fibrotic pathways. This identifies new therapeutic targets which have the potential to simultaneously decrease inflammation, tissue injury and fibrosis. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis

“…ROS can directly activate NF-κB and can also induce direct DNA damage in cells which might lead to HCC. 107 …”

Inflammasome activation and function in liver disease

“…The direct pathway is mediated by inflammasome expression in HSCs, the main profibrogenic cell population in the liver. 146,147 Canonical inflammasome activators, such as uric acid crystals, can activate primary mouse HSCs and human HSC lines. 146 Uric acid crystals upregulate transforming growth factor (TGF)-β1 expression, a major profibrogenic cytokine, activate HSCs, and induce production of collagen and its deposition into the extracellular matrix.…”

Cellular and molecular mechanisms in liver fibrogenesis

“…Pertinent to this review is the emerging evidence suggesting that this theoretically acute inflammatory pathway seems to be critical also for sustaining fibrogenesis in several organs including the lung, liver, and skin [114]. Whether CLDs are concerned, recent experimental studies, performed by means of selective depletion of macrophages, have outlined that macrophage activation in liver fibrosis has at least two distinct phases: a) during fibrogenic progression of CLDs liver macrophages contribute to the deposition of ECM components matrix; b) during fibrosis reversion macrophages contribute mainly to matrix degradation [115].…”

“…Indeed HSC express the critical inflammasome components and positively respond to classic DAMPs like uric acid crystals, which are known to activate NLRP3 inflammasome. Although uric acid crystals may represent somewhat "alien" DAMPs for HSC, exposure of either human or mouse HSC to these crystals results in a further change in morphology (more fibroblastoid phenotype) as well as in an increased expression of TGF-β and collagen type I, changes which do not occur in HSC lacking the adaptive protein Asc [114].…”