New dog and new tricks: evolving roles for IL-33 in type 2 immunity

Abstract

IL-33 is a more recently identified member of the IL-1 cytokine family, expressed in the nucleus of epithelial cells and released into the extracellular space following tissue damage. The impact of IL-33 as a regulator of the adaptive immune response has been studied extensively, with an understood role for IL-33 in the effector functions of CD4(+) Th2 cells. IL-33, however, is now being shown to initiate the Th2-polarizing function of DCs, and stimulate the secretion of the type 2-associated cytokines, IL-4, IL-5, and IL-13, from tissue-resident innate-immune cells, especially ILCs and MCs. IL-33 also initiates and perpetuates local inflammatory responses through the recruitment and activation of type 2- and inflammatory-associated effectors, such as eosinophils, basophils, and neutrophils. As such, IL-33 drives and amplifies type 2-dependent immunity, as well as type 2-dependent tissue destruction and inflammation. It is also becoming apparent that IL-33 supports the reparative capacity of macrophage and ILCs, but these functions may also contribute to chronic fibrotic diseases. Herein, we review new developments in the understanding of IL-33 as it functions in Th2 cells and type 2 immunity. This includes a discussion of our evolving understanding of how IL-33 directly and indirectly promotes type 2 immune responses through action on innate cells in immunity and the pathogenesis of atopic and fibrotic diseases.

Lipopolysaccharide Domains Modulate Urovirulence

“…IL-33 has been well established in helping skew adaptive immune responses toward a Th 2 response (54). Consistent with our hypothesis, we find that inoculation with the ⌬waaL LPS mutant does not result in the significant production of IL-33.…”

New insights into basophil heterogeneity

“…In addition to TSLP, IL-33, another epithelial-derived cytokine that potently promotes type-2 cytokine responses and associated allergic inflammation, regulates basophil function in the context of allergy [106,107]. Genome wide association studies have positively linked IL-33 in addition to TSLP to several allergic conditions like AD, asthma and food allergy [108,109].…”

Controlling the burn and fueling the fire

“…We have reviewed the basics of the molecular biology of IL-33 and its receptor complex elsewhere [2, 6]. In brief, like IL-1β or IL-18, IL-33 is synthesized with a typical IL-1 family 12-stranded β-trefoil C-terminal cytokine domain, but it also has a unique N-terminal nuclear localization sequence and chromatin-binding motif [1, 6].…”

“…As to be expected from these early observations, a role for endogenous IL-33 as a mediator of Type 2 immune pathologies helminth immunity and fibrotic disease has been soundly established [2]. Yet, convincing recent studies have also demonstrated the capacity of IL-33 to fuel the expansion of regulatory T cells (T reg ) and support T reg stability during inflammation [3].…”