Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner. https://www.ncbi.nlm.nih.gov/pubmed/26690128 full https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691098/ IL-33 AND MAST CELLS ARE THE BRIDGE BETWEEN THE INNATE AND AQUIRED IMMUNE SYSTEMS. The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses. The molecular mechanisms underlying the initiation of innate and adaptive proallergic Th2-type responses in the airways are not well understood. IL-33 is a new member of the IL-1 family of molecules that is implicated in Th2-type responses. Airway exposure of naive mice to a common environmental aeroallergen, the fungus Alternaria alternata, induces rapid release of IL-33 into the airway lumen, followed by innate Th2-type responses. Biologically active IL-33 is constitutively stored in the nuclei of human airway epithelial cells. Exposing these epithelial cells to A. alternata releases IL-33 extracellularly in vitro. Allergen exposure also induces acute extracellular accumulation of a danger signal, ATP; autocrine ATP sustains increases in intracellular Ca(2+) concentration and releases IL-33 through activation of P2 purinergic receptors. Pharmacological inhibitors of purinergic receptors or deficiency in the P2Y2 gene abrogate IL-33 release and Th2-type responses in the Alternaria-induced airway inflammation model in naive mice, emphasizing the essential roles for ATP and the P2Y(2) receptor. Thus, ATP and purinergic signaling in the respiratory epithelium are critical sensors for airway exposure to airborne allergens, and they may provide novel opportunities to dampen the hypersensitivity response in Th2-type airway diseases such as asthma. http://www.ncbi.nlm.nih.gov/pubmed/21357533/ The role of IL-33 and mast cells in allergy and inflammation. Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) cytokine family. It is preferentially and constitutively expressed in different structural cells such as epithelial cells, endothelial cells, and smooth muscle cells. During necrosis of these cells (after tissue injury or cell damage), the IL-33 that is released may be recognized by different types of immune cells, such as eosinophils, basophils and, especially, mast cells. IL-33 needs the specific receptor ST2 (membrane-bound receptor) and Interleukin-1 receptor accessory protein heterodimer for its binding, which instigates the production of different types of cytokines and chemokines that have crucial roles in the exacerbation of allergic diseases and inflammation. IL-33 and mast cells have been influentially associated to the pathophysiology of allergic diseases and inflammation. IL-33 is a crucial regulator of mast cell functions and might be an attractive therapeutic target for the treatment of allergic and inflammatory diseases. In this review, we summarize the current knowledge regarding the roles of IL-33 and mast cells in the pathogenesis of allergies and inflammation. http://www.ncbi.nlm.nih.gov/pubmed/26425339 FULL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588911/ Crucial and diverse role of the interleukin-33/ST2 axis in infectious diseases. Interleukin-33 (IL-33) has now emerged as a cytokine with diverse and pleiotropic functions in various infectious and inflammatory diseases. IL-33 is expressed by epithelial cells, endothelial cells, fibroblasts, and hepatocytes. The target cells of IL-33 are Th2 cells, basophils, dendritic cells, mast cells, macrophages, NKT cells, and nuocytes, newly discovered natural helper cells/innate lymphoid cells bearing the ST2 receptor. IL-33 has dual functions, both as a traditional cytokine and as a nuclear factor that regulates gene transcription. IL-33 functions as an "alarmin" released following cell death, as a biomarker, and as a vaccine adjuvant, with proinflammatory and protective effects during various infections. The exacerbated or protective role of the IL-33/ST2 axis during different infections is dependent upon the organ involved, type of infectious agent, whether the infection is acute or chronic, the invasiveness of the infectious agent, the host immune compartment, and cellular and cytokine microenvironments. In this review, we focus on recent advances in the understanding of the role of the IL-33/ST2 axis in various viral, bacterial, fungal, helminth, and protozoal infectious diseases gained from animal models and studies in human patients. The functional role of IL-33 and ST2 during experimentally induced infections has been summarized by accumulating the data for IL-33- and ST2-deficient mice or for mice exogenously administered IL-33. In summary, exploring the crucial and diverse roles of the IL-33/ST2 axis during infections may help in the development of therapeutic interventions for a wide range of infectious diseases. https://www.ncbi.nlm.nih.gov/pubmed/25712928/ FULL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399062/ In contrast to other IL-1 family cytokines, the full-length bioactive form of IL-33 is released by necrotic cells following cell damage or tissue injury and acts as an endogenous danger signal, or alarmin (3,–6). On the contrary, apoptotic caspases cleave IL-33 and destroy its bioactivity (3, 7). Despite this paradigm, IL-33 can also be released by living cells in its full-length bioactive form (8). IL-33 is constitutively expressed by tissue barrier cells, such as the epithelial and endothelial cells of many organs (1, 2), and it is also expressed in other cell types, including innate immune cells (1, 9), fibroblasts (5, 9, 10), and hepatocytes (11). Once secreted, IL-33 binds to its specific receptor, ST2. Membrane-bound ST2 recruits the IL-1 receptor accessory protein (IL-lRAcP), leading to the activation of MyD88 and the NF-κB signaling pathway (2), whereas soluble ST2 (sST2) is a decoy receptor of IL-33 (12). The target cells of IL-33 include B cells, T helper 2 (Th2) cells, T CD8+ cells, macrophages, dendritic cells, basophils, and a recently identified population of innate lymphoid cells called nuocytes in different tissues, including lungs, gut, liver, spleen, and skin (1, 13,–16). IL-33 is mainly associated with the initiation or progression of specific Th2 responses through secretion of IL-5 and IL-13. IL-33 contributes to macrophage alternative polarization, dendritic cell regulation, and direct effects on T cells (1, 17,–20). These pleiotropic effects explain how IL-33 plays contrasting roles in human diseases. It is deleterious in autoimmune diseases, such as rheumatoid arthritis (21, 22) or inflammatory bowel disease (23), and in asthma/allergic diseases (24, 25). However, IL-33 is cardio-protective and plays a beneficial role in metabolic diseases (26) and in many diseases associated with an exacerbated Th1 response, such as atherosclerosis (27). Although IL-33 has been extensively studied in the setting of various inflammatory diseases, a comprehensive overview on the role of this cytokine during infectious diseases is actually lacking. Therefore, based upon our findings and other published data, we have reviewed the role of the IL-33/ST2 axis during viral, bacterial, fungal, and parasitic infections in animal models and human patients.