Diverse innate stimuli activate basophils through pathways involving Syk and IκB kinases

Abstract

Mature basophils play critical inflammatory roles during helminthic, autoimmune, and allergic diseases through their secretion of histamine and the type 2 cytokines interleukin 4 (IL-4) and IL-13. Basophils are activated typically by allergen-mediated IgE cross-linking but also by endogenous “innate” factors. The aim of this study was to identify the innate stimuli (cytokines, chemokines, growth factors, hormones, neuropeptides, metabolites, and bacterial products) and signaling pathways inducing primary basophil activation. Basophils from naïve mice or helminth-infected mice were cultured with up to 96 distinct stimuli and their influence on basophil survival, activation, degranulation, and IL-4 or IL-13 expression were investigated. Activated basophils show a heterogeneous phenotype and segregate into distinct subsets expressing IL-4, IL-13, activation, or degranulation markers. We find that several innate stimuli including epithelial derived inflammatory cytokines (IL-33, IL-18, TSLP, and GM-CSF), growth factors (IL-3, IL-7, TGFβ, and VEGF), eicosanoids, metabolites, TLR ligands, and type I IFN exert significant direct effects on basophils. Basophil activation mediated by distinct upstream signaling pathways is always sensitive to Syk and IκB kinases-specific inhibitors but not necessarily to NFAT, STAT5, adenylate cyclase, or c-fos/AP-1 inhibitors. Thus, basophils are activated by very diverse mediators, but their activation seem controlled by a core checkpoint involving Syk and IκB kinases.

Interleukin 33-mediated inhibition of A-type K+ channels induces sensory neuronal hyperexcitability and nociceptive behaviors in mice

“…Consistent with this, preincubating DRG neurons with the JAK2-specific inhibitor AG490 (10 μM) did not influence the inhibitory effect of IL-33 on I A (decrease of 30.9 ± 4.2%, Figure 3 C). It has been demonstrated that Syk is a nonreceptor tyrosine kinase involved in several cytokine signaling pathways 42 , 43 . Immunoblot analysis of DRG cell lysates revealed the protein expression of Syk (Figure 3 D & Figure S5 ), and immunofluorescence staining showed that Syk was coexpressed with ST2 (Figure 3 B).…”

SARS-CoV-2 Induces Cytokine Responses in Human Basophils

“…These receptors are highly expressed by epithelial cells that are present in the lungs and gastrointestinal tract. Several innate stimuli including epithelial derived inflammatory cytokines (IL-33, IL-18, Thymic stromal lymphopoietin, and GM-CSF), growth factors (IL-3, IL-7, TGF-β, and VEGF) activate the mouse basophils ( 57 ). Also, airway epithelial cell line A549 has been reported to induce activation of human basophils ( 18 ).…”

Immunology of Acute and Chronic Wound Healing

“…Various T cells subsets are found in acute wounds and are responsible for bacterial elimination, modulation of immune responses and tissue remodeling. Basophils are one of the first cells that infiltrate into the injured tissue attracted by endogenous factors, such as IL-33, IL-18, thymic stromal lymphopoietin (TSLP), granulocytemacrophage colony-stimulating factor (GM-CSF), IL-3, IL-7, TGF-β, VEGF and IFN type I [43]. They are the major producers of IL-4, the cytokine which is known to facilitate fibroblast proliferation and chemotaxis as well as the production of collagen and ECM molecules in skin wounds [44,45].…”