IL-33/ST2 axis promotes mast cell survival via BCLXL

Abstract

Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues. MC express the IL-33 receptor IL-1 receptor-related protein ST2 at high level, and this IL-1 family cytokine both activates MC directly and primes them to respond to other proinflammatory signals. Whether IL-33 and ST2 play a role in MC survival remains to be defined. In skin-derived human MC, we found that IL-33 attenuated MC apoptosis without altering proliferation, an effect mediated principally through the antiapoptotic molecule B-cell lymphoma-X large (BCLXL). Murine MC demonstrated a similar mechanism, dependent entirely on ST2. In line with these observations, St2−/− mice exhibited reduced numbers of tissue MC in inflamed arthritic joints, in helminthinfected intestine, and in normal peritoneum. Together, these data reveal a cell-intrinsic role for the IL-33/ST2 axis in the regulation of apoptosis in MC, identifying thereby a previously unappreciated pathway supporting expansion of the MC population with inflammation.arthritis | helminth infection M ast cells (MC) are tissue-resident effector cells that contribute both to innate and adaptive immunity (1). MC help defend against bacterial and helminthic infection (2, 3) and play a role in tissue remodeling (4, 5). MC can also contribute to a variety of allergic and nonallergic inflammatory diseases, such as anaphylaxis, atopic dermatitis, asthma, inflammatory arthritis, psoriasis, and multiple sclerosis (6, 7). Under many of these conditions, the number of MC in affected tissues increases by tenfold or more, amplifying the contribution of MC-derived mediators to ongoing inflammation (6-8). Regulation of the MC population is poorly understood, and therapeutic intervention to limit MC accumulation potentially could attenuate injury associated with inflammatory diseases (9, 10).The survival of mature MC in tissues depends on signals from neighboring cells (11,12). The single most important mediator in this process is stem cell factor (SCF), a master regulator of MC proliferation, differentiation, survival, and activation. Mice with genetic mutations affecting SCF or its receptor Kit have few or no MC in healthy or inflamed tissues, whereas activating mutations of Kit give rise to pathologic mastocytosis (13-15). IL-3 is another well-recognized MC growth factor (16). SCF/Kit and IL-3 interface with several antiapoptotic pathways, up-regulating the antiapoptotic protein B-cell lymphoma-2 (BCL-2) and downregulating the proapoptotic protein Bim (14,(17)(18)(19). Aside from SCF/Kit and IL-3, other cytokines have been reported to support MC survival, but their effects appear to be restricted to specific MC subtypes. IL-4 promotes survival of intestinal MC via both BCL-2 and B-cell lymphoma-X large (BCLXL) but may suppress survival in human cord blood MC as well as murine bone marrowderived MC (BMMC) (20-23). IL-10 can either promote or impair survival depending on the type of MC studied (21,22).Recently, substantial attention has focused on the role of IL-33 in MC biolog...

The role of IL-33/ST2L signals in the immune cells

“…Actually, many cytokines can support MCs survival, and their effects are restricted to specific MCs subtype. IL-33 promotes the survival of both human and murine MCs, mediated principally by up-regulation of the antiapoptotic factor B-cell lymphoma-X large (BCLXL) [12] (Fig. 3).…”

“…ST2L is expressed on many immune cells including macrophages [10], T cells particularly Th2 [11], mast cells [12], and innate lymphoid cells (ILCs) [13]. IL-33/ST2L signals are involved in the regulation of T cells and DCs differentiation, activation of macrophages and mast cells, promotion of Th2 cytokine production by ILCs [14][15][16][17][18].…”

Non-IgE mediated mast cell activation

“…It is expressed primarily by stromal cells, such as epithelial cells, and released upon cell damage (Wang et al, 2014). IL-33 modulates various aspects of mast cell function, including adhesion, survival, maturation and activation, through activation of the cell surface ST2 (IL-1RL1).…”

“…IL-33 modulates various aspects of mast cell function, including adhesion, survival, maturation and activation, through activation of the cell surface ST2 (IL-1RL1). For instance, (1) adhesion: IL-33, together with IL-1β, enhances the adhesion of human CBMC to fibronectin (Iikura et al, 2007); (2) survival: IL-33 attenuates human skin mast cell apoptosis through the anti-apoptotic molecule B-cell lymphoma-X large (BCLXL), raising the possibility of IL-33/ST2 axis as a potential target to limit mast cells in chronic inflammatory diseases (Wang et al, 2014); (3) maturation: the addition of IL-33 to in vitro cultures accelerates the maturation of CD34 + mast cell precursors into tryptase-containing cells (Allakhverdi et al, 2007); (4) activation: IL-33 exacerbates antigen-induced arthritis activating mast cells in a murine model (Xu et al, 2008); it can also synergize with IgE or IgE-independent agents, such as adenosine, C5a, SCF, NGF, PMA and TSLP, in the activation of HMC-1 (Silver et al, 2010). However, it should be noted that long exposure to IL-33 in in vitro cultures can lead to a hypo-responsive phenotype of both human and mouse mast cells (Sibilano et al, 2014).…”

News in Cellular Allergology: A Review of the Human Mast Cell and Basophil Granulocyte Literature from January 2013 to May 2015

“…IL33 is a survival factor for mast cells [10] that does not induce degranulation of mast cells or basophils, but is released during activation of these cells [11]. TSLP (thymic stromal lymphopoietin) and IL33 synergise with IgE to enhance Cys-LT, but not PGD2 synthesis in human cord blood-derived mast cells [12].…”