Human Lung Mast Cells: Therapeutic Implications in Asthma

Abstract

Mast cells are strategically located in different compartments of the lung in asthmatic patients. These cells are widely recognized as central effectors and immunomodulators in different asthma phenotypes. Mast cell mediators activate a wide spectrum of cells of the innate and adaptive immune system during airway inflammation. Moreover, these cells modulate the activities of several structural cells (i.e., fibroblasts, airway smooth muscle cells, bronchial epithelial and goblet cells, and endothelial cells) in the human lung. These findings indicate that lung mast cells and their mediators significantly contribute to the immune induction of airway remodeling in severe asthma. Therapies targeting mast cell mediators and/or their receptors, including monoclonal antibodies targeting IgE, IL-4/IL-13, IL-5/IL-5Rα, IL-4Rα, TSLP, and IL-33, have been found safe and effective in the treatment of different phenotypes of asthma. Moreover, agonists of inhibitory receptors expressed by human mast cells (Siglec-8, Siglec-6) are under investigation for asthma treatment. Increasing evidence suggests that different approaches to depleting mast cells show promising results in severe asthma treatment. Novel treatments targeting mast cells can presumably change the course of the disease and induce drug-free remission in bronchial asthma. Here, we provide an overview of current and promising treatments for asthma that directly or indirectly target lung mast cells.

Airway remodelling in asthma and the epithelium: on the edge of a new era

“…T2 inflammation, involving eosinophils, mast cells, ILC2s, Th2 cells and basophils, contributes to airway remodelling in most patients with severe asthma [ 128 , 186 , 187 ]. The contribution of non-T2 inflammation to airway remodelling, presumably involving mast cells, macrophages and neutrophils [ 49 , 63 ], remains to be fully clarified [ 186 , 188 , 189 ].…”

Basophils beyond allergic and parasitic diseases

“…Relative to asthma, the cellular and molecular mechanisms of COPD remain ill defined ( 117 ). It also differs in being characterized by a non-reversible airway obstruction ( 82 , 218 ).…”

“…Finally, several biologics have been approved for the treatment of severe allergic disorders and are showing remarkable efficacy ( 218 ). Those designed primarily to target mast cells, eosinophils, and Th2 cells (e.g., omalizumab, mepolizumab, benralizumab and dupilumab) also target human basophils and/or their products ( 250 , 277 ).…”

Mast Cells in Upper and Lower Airway Diseases: Sentinels in the Front Line

“…Moreover, biologics that bind MCs and eosinophils' surface molecules and eventually cause antibody-mediated cytotoxicity of these cells (e.g., lirentalimab, which targets sialic acid-binding Ig-like lectin 8) are under assessment for the treatment of type 2 inflammatory diseases, including asthma [119]. Another field of investigation in MC-mediated disorders are drugs that inhibit KIT activity, resulting in MC apoptosis and depletion, which can be achieved through monoclonal antibodies (e.g., CDX-0159) or small molecules (e.g., imatinib) [145]; the latter was able to decrease airway responsiveness, MC counts, and tryptase release compared to placebo in a proof-of principle trial on severe asthma patients [146]. Another interesting approach would be to inhibit intracellular transduction pathways that mediate immune cell activation, including of MCs, for example, through the blockade kinases (e.g., Janus kinase, Bruton's tyrosine kinase, spleen tyrosine kinase).…”

“…To conclude, the potential targets to inhibit MCs in asthma and other MC-mediated disorders are numerous and it is likely that in near future novel therapies will be available. A better understanding of MCs' biology and complex phenotypic heterogenicity is critical to provide further insights to drive further research in drug development [145].…”