IL-33/ST2 Axis in Organ Fibrosis

Abstract

Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.

Deciphering the cellular interplays underlying obesity-induced adipose tissue fibrosis

“…Through the production of IL-33, IL-33 + progenitor subsets function to control the accumulation of regulatory T cells in the adipose tissue, suggesting progenitors as an important orchestrator of the tissular immunological response (126). In addition, IL-33 was shown to be a positive inducer of fibrosis in lung and liver (127).…”

Occupation versus environmental factors in hypersensitivity pneumonitis: population attributable fraction

“…More broadly, because serum CC16 may be a marker of increased leakage across the alveolar barrier, this makes plausible an association with HP [31]. The biomarker sST2, although most frequently studied in cardiac injury, may play a role in various disease states, with particular relevance to inflammation and fibrosis [32]. Even though sST2 was not associated with HP in multivariate analysis of the entire group, it was statistically associated with HP in the tertiary referral case stratum.…”

NLRP3 Inflammasome-Mediated Inflammation in Acute Pancreatitis

“…Although several lines of evidence demonstrate a role for IL33 in fibrogenesis during chronic pancreatitis [95], investigations into the potential function of IL33 in the pathogenesis of AP are limited. As in IL1β and IL18, serum levels of this cytokine are increased in patients at the early stage of AP and correlate with AP severity.…”