Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

Abstract

Mast cells are often regarded through the lens of IgE-dependent reactions as a cell specialized only for anti-parasitic and type I hypersensitive responses. However, recently many researchers have begun to appreciate the expansive repertoire of stimuli that mast cells can respond to. After the characterization of the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis of mast cell activation—a pathway that is independent of the adaptive immune system—researchers are revisiting other stimuli to induce mast cell activation and/or subsequent degranulation independent of IgE. This discovery also underscores that mast cells act as important mediators in maintaining body wide homeostasis, especially through barrier defense, and can thus be the source of disease as well. Particularly in the gut, inflammatory bowel diseases (Crohn’s disease, ulcerative colitis, etc.) are characterized with enhanced mast cell activity in the context of autoimmune disease. Mast cells show phenotypic differences based on tissue residency, which could manifest as different receptor expression profiles, allowing for unique mast cell responses (both IgE and non-IgE mediated) across varying tissues as well. This variety in receptor expression suggests mast cells respond differently, such as in the gut where immunosuppressive IL-10 stimulates the development of food allergy or in the lungs where transforming growth factor-β1 (TGF-β1) can enhance mast cell IL-6 production. Such differences in receptor expression illustrate the truly diverse effector capabilities of mast cells, and careful consideration must be given toward the phenotype of mast cells observed in vitro. Given mast cells’ ubiquitous tissue presence and their capability to respond to a broad spectrum of non-IgE stimuli, it is expected that mast cells may also contribute to the progression of autoimmune disorders and other disease states such as metastatic cancer through promoting chronic inflammation in the local tissue microenvironment and ultimately polarizing toward a unique Th17 immune response. Furthermore, these interconnected, atypical activation pathways may crosstalk with IgE-mediated signaling differently across disorders such as parasitism, food allergies, and autoimmune disorders of the gut. In this review, we summarize recent research into familiar and novel pathways of mast cells activation and draw connections to clinical human disease.

Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

“…The latter receptor can be activated by a wide range of agonists, including neuropeptides (e.g., Substance P) and exogenous substances (like compound 48/80, antibiotics, opiates) [ 3 , 4 , 5 , 6 , 7 , 8 ]. The efficient triggering of MC degranulation and the large number of ligands have moved MRGPRX2 to the center of attention in recent years [ 9 , 10 , 11 , 12 , 13 , 14 ]. In fact, the receptor is now widely believed to constitute a major participant in drug-induced pseudo-allergic/anaphylactoid phenomena and in MC-dependent diseases triggered by exogenous or endogenous neuro-, host defense, and other peptides [ 4 , 6 , 15 , 16 ].…”

Mast Cells in Diabetes and Diabetic Wound Healing

“…From being known for their detrimental role in allergic diseases, such as food allergies, asthma, and anaphylaxis, for decades; to now recognized as crucial players in a diverse array of physiological and pathologic functions, including vasodilation, angiogenesis, lymphangiogenesis, pathogen elimination, innate and adaptive immune responses, wound healing, and homeostasis. Moreover, MCs play an important role in many diseases, such as gastrointestinal disorders, diabetes, malignancies, and cardiovascular diseases [ 3 – 6 ]. However, to this day, the pathophysiological roles of MCs are not well understood.…”

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

“…MC's are first responders during infections, where IL33 acts as an alarmin following its release as a cellular danger signals ( 49 ). The dual importance of IL33 and MCs in allergies is well established ( 50 ), yet critical roles for the IL33-MC axis have also been uncovered in allergic, autoimmune, inflammatory disease as well as cancer and other diseases ( 51 , 52 ). In addition, MCs can potentiate the biological impact of IL33, because chymases and tryptases released by activated MCs process full-length IL33 into a truncated and biologically more active mature protein ( 53 ).…”

“…Allergen IgE-mediated activation of MCs was the first to be identified and is well characterized in the context of allergic pathologies, yet many other factors can activate MCs in an IgE-independent manner ( 52 , 139 ).…”