Emerging mechanisms contributing to mast cell-mediated pathophysiology with therapeutic implications

Falduto, Guido H.; Pfeiffer, Annika; Luker, Andrea; Metcalfe, Dean D.; Olivera, Ana

doi:10.1016/j.pharmthera.2020.107718

Cited by 37 publications

(25 citation statements)

References 177 publications

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“…Basophils and mast cells often take the center stage in food allergy as predominant effector cells in IgE-mediated responses. In addition, their rapid responses to bacterial products and mediators released by damaged epithelium position them at the crossroads between the innate and adaptive arms of the immune system, as innate stimulation can alter their responses to antibody cross-linking (7)(8)(9). Several articles in this Research Topic summarize critical knowledge on aspects of basophil/mast cell activation, roles in food allergy, utility as diagnostic tools, and targets for pharmacological intervention.…”

Section: The Role Of Basophils and Mast Cellsmentioning

confidence: 99%

Editorial: Innate Cells in the Pathogenesis of Food Allergy

et al. 2021

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Editorial on the Research TopicInnate Cells in the Pathogenesis of Food Allergy Food allergy results from a failure to establish or maintain oral tolerance to certain food proteins and is manifested by adverse responses following ingestion of these foods that range from mild to life-threatening. The increasing prevalence in pediatric and adult food allergy in recent decades and the potentially life-threatening nature of reactions make food allergy a significant public health concern (1). Clinical data and experimental studies establish a role for the adaptive immune system, particularly food-specific IgE, in food allergy. Emerging evidence indicates that innate cells, nonadaptive immune processes, and environmental factors including diet, drugs, and exercise also contribute to abnormal responses to food (2, 3). However, precisely how innate cells, non-adaptive immune processes and factors impact the food allergy diathesis remains poorly understood.This Frontiers Research Topic represents a collection of articles from worldwide experts that collectively present a current overview of mechanisms in food allergy, diagnostics, and treatments, with particular emphasis on the roles played by innate immune cells. We received a total of 16 articles, including 8 Reviews and 1 Perspective on central topics to food allergy and eosinophilic esophagitis (EoE); and 7 Original Research articles that describe various mechanistic aspects and involvement of innate cells, mediators, microbiota, and factors that alter responses to food in mouse models and humans.

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Section: The Role Of Basophils and Mast Cellsmentioning

confidence: 99%

Editorial: Innate Cells in the Pathogenesis of Food Allergy

et al. 2021

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“…Mast cells are innate immune component cells distributed around blood vessels and nerves ( 28 ). Activation of mast cells can be triggered by various extracellular stimuli like antigen-IgE complex, cytokines expressed by other inflammatory cells, viruses, bacteria, and microvesicles ( 29 , 30 ). Many past and recent studies have emphasized that IgE-dependent mast cell degranulation plays a crucial role in CSU, which could be promoted by various outer factors (cold, heat, pressure) or allergens ( 31 – 33 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of Crosstalk of Immune Cells in Pathogenesis of Chronic Spontaneous Urticaria

Zhou

et al. 2022

Front. Immunol.

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Chronic spontaneous urticaria (CSU) is defined as recurrent episodes of spontaneous wheal development and/or angioedema for more than six weeks and at least twice a week. The core link in the pathogenesis of CSU is the activation of mast cells, T cells, eosinophils, and other immune cells infiltrating around the small venules of the lesion. Increased vascular permeability, vasodilatation, and recruitment of inflammatory cells directly depend on mast cell mediators’ release. Complex regulatory systems tightly influence the critical roles of mast cells in the local microenvironment. The bias toward Th2 inflammation and autoantibodies derived from B cells, histamine expressed by basophils, and initiation of the extrinsic coagulation pathway by eosinophils or monocytes exerts powerful modulatory influences on mast cells. Cell-to-cell interactions between mast cells and eosinophils/T cells also are regulators of their function and may involve CSU’s pathomechanism. This review summarizes up-to-date knowledge regarding the crosstalk between mast cells and other immune cells, providing the impetus to develop new research concepts and treatment strategies for CSU.

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“…Mast cells are immune cells of the myeloid lineage with key roles in the initiation of allergic reactions and in the regulation of chronic inflammation. Activated mast cells mediate these functions through the release of a vast variety of vasoactive and immune-modulatory molecules ( 1 ). The severity of mast cell-mediated reactions generally depends on the extent and duration of mast cell responses, and it is influenced by the number of mast cells in tissues ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…Mast cells terminally differentiate in tissues, where they take up long-term residence. Mast cell numbers are increased in allergic disorders such as asthma, allergic rhinitis, food allergy and atopic dermatitis ( 2 , 3 ), partly due to enhanced recruitment of mast cell progenitors to the affected sites followed by their maturation ( 1 , 4 , 5 ). Abnormal increases in mast cells are also seen in other mast cell disorders such as mastocytosis, where clonal expansion of mast cells occurs in organs such as the skin, bone marrow and the gastrointestinal tract among others, in association with somatic activating mutations in the tyrosine kinase receptor KIT (CD117) ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

A Critical Function for the Transcription Factors GLI1 and GLI2 in the Proliferation and Survival of Human Mast Cells

et al. 2022

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Mast cell hyperactivity and accumulation in tissues are associated with allergy and other mast cell-related disorders. However, the molecular pathways regulating mast cell survival in homeostasis and disease are not completely understood. As glioma-associated oncogene (GLI) proteins are involved in both tissue homeostasis and in the hematopoietic system by regulating cell fate decisions, we sought to investigate the role for GLI proteins in the control of proliferation and survival of human mast cells. GLI1 transcripts were present in primary human mast cells and mast cell lines harboring or not activating mutations in the tyrosine kinase receptor KIT (HMC-1.1 and HMC-1.2, and LAD2 cells, respectively), while GLI2 transcripts were only present in HMC-1.1 and HMC-1.2 cells, suggesting a role for oncogenic KIT signaling in the regulation of GLI2. Reduction in GLI activity by small molecule inhibitors, or by shRNA-mediated knockdown of GLI1 or GLI2, led to increases in apoptotic cell death in both cultured human and murine mast cells, and reduced the number of peritoneal mast cells in mice. Although GLI proteins are typically activated via the hedgehog pathway, steady-state activation of GLI in mast cells occurred primarily via non-canonical pathways. Apoptosis induced by GLI silencing was associated with a downregulation in the expression of KIT and of genes that influence p53 stability and function including USP48, which promotes p53 degradation; and iASPP, which inhibits p53-induced transcription, thus leading to the induction of p53-regulated apoptotic genes. Furthermore, we found that GLI silencing inhibited the proliferation of neoplastic mast cell lines, an effect that was more pronounced in rapidly growing cells. Our findings support the conclusion that GLI1/2 transcription factors are critical regulators of mast cell survival and that their inhibition leads to a significant reduction in the number of mast cells in vitro and in vivo, even in cells with constitutively active KIT variants. This knowledge can potentially be applicable to reducing mast cell burden in mast cell-related diseases.

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Emerging mechanisms contributing to mast cell-mediated pathophysiology with therapeutic implications

Cited by 37 publications

References 177 publications

Editorial: Innate Cells in the Pathogenesis of Food Allergy

Editorial: Innate Cells in the Pathogenesis of Food Allergy

The Role of Crosstalk of Immune Cells in Pathogenesis of Chronic Spontaneous Urticaria

A Critical Function for the Transcription Factors GLI1 and GLI2 in the Proliferation and Survival of Human Mast Cells

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