Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

Abstract

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.

Reparative T lymphocytes in organ injury

“…IL-33-stimulated Tregs upregulated reparative AREG production by ST2 + Tregs, contributing to the reprogramming of infiltrating macrophages to a pro-repair phenotype (51,52). IL-33/ST2 signaling can mediate tissue-reparative functions in the resolution phase after injury in different organ systems, although it may play pathological roles in type 2 diseases such as skin and lung allergic pathologies (53)(54)(55). Moreover, Treg contact-dependent and -independent cellular interactions with epithelial, endothelial, fibroblast, or other stromal cells can mediate their reparative effector functions.…”

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

“…Three distinct strategies for therapeutic targeting of the IL‐33/ST2 axis are currently in development: soluble decoy receptors, IL‐33 neutralizing antibodies, and anti‐ST2 blocking antibodies . Anti‐IL‐33 and anti‐ST2 antibodies are currently under evaluation in clinical trials for a range of allergic conditions including asthma, atopic dermatitis, peanut allergy, chronic rhinosinusitis with nasal polyps, as well as in COPD (Table ).…”

Novel Biomarkers in Patients with Chronic Kidney Disease: An Analysis of Patients Enrolled in the GCKD-Study

“…Hence, the adjustment for renal function may be more valid for biomarkers, which do not primarily correlate with renal function. Interestingly, although the ST2/IL-33 signaling pathway seems to be involved in various inflammatory processes [63][64][65][66], the aforementioned study by Alam et al did not find a statistically significant association of the plasma levels of sST2 with the progression of CKD to end-stage renal disease (ESRD) [60]. Taken together with our results, it seems as if sST2, in contrast to numerous other cytokines or mediators, acts relatively independent from renal function and pathophysiologic processes affecting the kidneys.…”