IL‐3–producing basophils are required to exacerbate airway hyperresponsiveness in a murine inflammatory model

• Published in: Allergy (Copenhagen) 2018-12, Vol.73 (12), p.2342-2351
• Main Authors: Rignault‐Bricard, R., Machavoine, F., Mecheri, S., Hermine, O., Schneider, E., Dy, M., Leite‐de‐Moraes, M.
• Format: Article
• Language: English
• Subjects: Adaptive immunology; Adoptive transfer; Allergology; Asthma; Autocrine signalling; basophils; Bone marrow; Calcineurin; Calcium; Calcium channels; Cytokines; Exposure; Gene expression; Histamine; Hypersensitivity; IL‐3; Immunoglobulin E; Immunology; Inflammation; Innate immunity; Leukocytes (basophilic); Life Sciences; Lymphocytes T; Mice; Microbiology and Parasitology; Ovalbumin; Parasitology; Respiratory tract; Therapeutic applications; Vaccinology
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/all.13480

Background Basophils are commonly associated with allergic responses because of their ability to produce large amounts of pro‐Th2 cytokines and histamine. However, the mechanisms through which bone marrow‐resident basophils (BMRB) become fully competent cytokine and histamine producers in response to IgE crosslinking are poorly understood. Here, we sought to determine the role of IL‐3 in promoting pro‐Th2 basophils. Methods BMRB and basophils exposed to IL‐3 in vitro and in vivo were evaluated for their production of Th2 cytokines and histamine in response to FcεRI crosslinking on both protein and gene expression levels. In vivo relevance of our findings was assessed in a model of ovalbumin‐induced allergic asthma using IL‐3–deficient and wild‐type mice in a protocol of adoptive basophil transfer. Results We show that BMRB and basophils previously exposed to IL‐3 differ in their ability to generate cytokines (IL‐4, IL‐6, IL‐13, and GM‐CSF) and histamine in response to FcεRI crosslinking, reflecting two stages of maturation. Exposure to IL‐3 initiated an autocrine loop of endogenous IL‐3 production that enhanced histamine and cytokine production upon FcεRI crosslinking. This increased responsiveness required calcium flux and was dependent on calcineurin and store‐operated calcium channels. Our findings are of pathophysiological relevance, as assessed by the failure of IL‐3–deficient mice to develop airway hyperreactivity, which could be restored by adoptive transfer of IL‐3–derived basophils recovered from wild‐type mice. Conclusion IL‐3–dependent basophils promote Th2 allergic AHR, which designates the IL‐3/basophil axis as a promising therapeutic target for the treatment of basophil‐dependent asthma. FcεRI crosslinking on IL‐3–derived basophils induces concomitant histamine and cytokine synthesis depending on calcineurin and store‐operated calcium entry. Autocrine IL‐3 is essential for enhancing the responsiveness of bone marrow basophils to FcεR1 crosslinking. IL‐3–deficient mice are unable to develop asthmatic hyperreactivity, which can be fully restored by the adoptive transfer of IL‐3–producing basophils.