Divergent Effects of Acute and Prolonged Interleukin 33 Exposure on Mast Cell IgE-Mediated Functions

Abstract

Background: Epithelial cytokines, including IL-33 and Thymic stromal lymphopoietin (TSLP), have attracted interest because of their roles in chronic allergic inflammation-related conditions such as asthma. Mast cells are one of the major targets of IL-33, to which they respond by secreting cytokines. Most studies performed thus far have investigated the acute effects of IL-33 on mast cells. In the current study, we investigated how acute vs. prolonged exposure of mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation. Methods: Human lung mast cells (HLMCs), cord blood-derived mast cells (CBMCs), and the ROSA mast cell line were used for this study. Receptor expression and the levels of mediators were measured after treatment with IL-33 and/or TSLP. Results: IL-33 induced the release of cytokines. Prolonged exposure to IL-33 increased while TSLP reduced intracellular levels of tryptase. Acute IL-33 treatment strongly potentiated IgE-mediated activation. In contrast, 4 days of exposure to IL-33 decreased IgE-mediated activation, an effect that was accompanied by a reduction in FcεRI expression. Conclusion: We show that IL-33 plays dual roles in mast cells, in which its acute effects include cytokine release and the potentiation of IgE-mediated degranulation, whereas prolonged exposure to IL-33 reduces IgE-mediated activation. We conclude that mast cells act quickly in response to the alarmin IL-33 to initiate an acute inflammatory response, whereas extended exposure to IL-33 during prolonged inflammation reduces IgE-mediated responses. This negative feedback effect suggests the presence of a novel regulatory pathway that modulates IgE-mediated human mast cell responses.

GM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis

“…In addition, MC were detected in the synovial fluid in a higher proportion of SpA patients compared to patients with other forms of arthritis 66 . Similarly to our observations in mice, a promoting effect of IL-33 on GM-CSF secretion by human MC has been reported in several studies 48,67 , supporting the potential relevance of the MC-mediated IL-33/ GM-CSF axis to the inflammatory response to humans. Consequently, MCs may represent a promising therapeutic target for SpA, with a recent pilot study suggesting this approach could be safe and effective 68 .…”

Thymic Stromal Lymphopoietin Interferes with the Apoptosis of Human Skin Mast Cells by a Dual Strategy Involving STAT5/Mcl-1 and JNK/Bcl-xL

“…Han et al described an antiapoptotic effect in the human MC line (HMC)-1 (as well as in the immature murine bone marrow-derived mast cell (BMMC) [27], while human lung MCs did not experience survival promotion by TSLP [25]. Together, this indicates that immaturity and/or malignant transformation may have pre-disposed to survival rescue by TSLP, which is also in accordance with a recent finding of increased TSLPR expression in the continuously growing MC line ROSA vis-à-vis primary MCs [28]. However, because skin MCs, not studied previously, represent primary, fully differentiated MCs, just like lung MCs, our current data instead imply that MCs at a post-maturation stage are amenable to survival protection by TSLP and that the microenvironment in which they completed maturation will primarily dictate this response.…”

“…TSLP notably contributes to skin disorders like AD [20,54], and accordingly, binding to its specific receptor has been reported to regulate selected aspects of MC biology, including maturation and mediator secretion [24,25,26,27]. In this regard, Lai et al demonstrated that TSLP can increase Tryptase storage [55], whereas Rönnberg et al showed an opposite effect [28], underlining the heterogeneous character of MCs. Han et al described an antiapoptotic effect in the human MC line (HMC)-1 (as well as in the immature murine bone marrow-derived mast cell (BMMC) [27], while human lung MCs did not experience survival promotion by TSLP [25].…”

“…While the responsiveness of MCs to TSLP has been occasionally reported [24,25,26,27,28], it remains to be established if and how MCs of human skin origin are targeted by TSLP. This is of relevance because MCs are known for their highly heterogeneous nature [7,29,30], so that their response pattern will depend on the precise MC subset and location.…”

IL33 and Mast Cells—The Key Regulators of Immune Responses in Gastrointestinal Cancers?

“…Numerous studies have shown that IL33-elicited responses in MCs differ from IgE stimulation and that IL33-mediated responses in MCs are modified, and often potentiated, when secondary stimuli like IgE, substance P or IL3 are present (112,(141)(142)(143)(144). Further research is required to uncover other MC-activating factors present in the tumor microenvironment and how they impact IL33 signaling and MC activation.…”