Signalling mechanisms regulating the activation of human eosinophils by mast‐cell‐derived chymase: implications for mast cell–eosinophil interaction in allergic inflammation

Abstract

Allergic diseases such as asthma and allergic dermatitis are associated with the degranulation of mast cells. Chymase, a mast-cell-specific protease, is the major component in mast cell granules that can induce eosinophil infiltration into inflammatory sites. We examined the immunopathological mechanisms for the activation of eosinophils by chymase in allergic inflammation. Cytokines were measured by cytometric bead array Flex Sets multiplex assay using flow cytometry and enzyme-linked immunosorbent assay. Adhesion molecules, migration and intracellular signalling pathways were assessed by flow cytometry, Boyden chamber assay and Western blot, respectively. Chymase suppressed the apoptosis of eosinophils and induce the release of the cytokine interleukin-6 (IL-6) and chemokines CXCL8, CCL2 and CXCL1 by eosinophils dose-dependently. It also up-regulated the surface expression of adhesion molecule CD18 and stimulated the chemokinetic migration of eosinophils. The expressions of adhesion molecules, cytokines and chemokines, and chemokinetic migration were differentially regulated by the activation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, Akt, Janus-activated kinase and nuclear factor-kappaB pathways. Chymase therefore plays a pivotal immunological role in the interaction between mast cells and eosinophils in allergic diseases such as allergic dermatitis by inducing adhesion molecule-mediated chemokinetic migration and inflammatory cytokines and chemokines of eosinophils, through multiple intracellular signalling molecules and transcription factor. Our results therefore provide a further biochemical basis for the pathogenesis of allergic inflammation consequent on the interaction between mast cells and eosinophils, and give insight for the development of new therapies.

Human Eosinophils Express the High Affinity IgE Receptor, FcεRI, in Bullous Pemphigoid

“…Interpretation of these studies is limited by the fact that samples were a mixed population of granulocytes and do not rule out the possibility that eosinophil degranulation could be mediated indirectly by factors released upon basophil degranulation. Indeed, we have previously shown via histamine release that BP basophils degranulate upon exposure to BP180 [2], and basophil derived mediators could also trigger eosinophil degranulation [60]. To investigate the possibility of indirect eosinophil degranulation, triggered by mast cells, degranulation of immunomagnetically purified (≥94%) eosinophils has been examined on a limited number (3 BP, 3 control) of samples.…”

Pneumoviruses infect eosinophils and elicit MyD88-dependent release of chemoattractant cytokines and interleukin-6

“…We also show that RSV infection of human eosinophils results in the replication-dependent release of IL-6, a cytokine localized to specific granules 50 and released in response to mast cell chymase, IL-23, and various TLR ligands. [51][52][53] Although the precise role of IL-6 in the overall clinical picture of RSV disease has not been discerned, Bennett et al 54 and Oh et al 55 independently evaluated intranasal samples from patients with RSV and other virus infections and found elevated levels of proinflammatory cytokines, including IL-6.…”

Eosinophils in innate immunity: an evolving story

“…An “eosinophil-mast cell axis” has been described whereby the two innate immune leukocytes interact to enhance their respective capabilities. The mast cell-specific protease chymase recruits eosinophils into tissue sites, suppresses eosinophil apoptosis, and promotes the secretion of eosinophil-derived cytokines and chemokines (Wong et al 2009). Mast cells also secrete eosinophilopoietins including GM-CSF, IL-3, IL-5 and TNF-α (Levi-Schaffer et al 1998; Shakoory et al 2004).…”