A common signaling pathway leading to degranulation in mast cells and its regulation by CCR1‐ligand

Abstract

Abbreviations: A770041, a selective inhibitor of Lck; Ag, antigen; BMMC, bone marrow-derived mast cells; CCL3, C-C motif chemokine ligand 3; DNP-HSA, dinitrophenyl-human serum albumin; eMIP, a 69-amino acid variant of human CCL3; ERK/Erk1/2, extracellular signal-regulated kinase 1/2; Fexo, fexofenadine; GPCR, G protein-coupled receptor; HSP, heat shock proteins; HSP70, heat shock protein 70; IgE, immunoglobulin E; IKK, IκB kinase; IL-6, interleukin-6; IRF, interferon regulatory factor; JNK, c-Jun N-terminal kinase; KIT, c-kit receptor; KO, knockout; LAT, linker for activation of T cells; Lck, lymphocyte-specific protein tyrosine kinase; LTC 4 , leukotriene C 4 ; MAPK, mitogen-activated protein kinase; M-dose, micromolar doses; MyD88, myeloid differentiation factor 99; N-dose, nanomolar doses; NF-κB, nuclear factor-kappa B; NK, natural killer; PCA, passive cutaneous anaphylaxis or anaphylactic; PGD 2 , prostaglandin D 2 ; Phospho-Lck, phosphorylated Lck; Phospho-Syk, phosphorylated Syk; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLCγ, phospholipase Cγ; SCF, stem cell factor; SHP-1, Src homology region 2 domain-containing phosphatase-1; Syk, spleen tyrosine kinase; TIR domain, Toll/interleukin-1 receptor homology domain; TIRAP, TIR domain-containing adaptor protein; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor-α; TRAF6, TNF receptor-associated factor 6; β-Hex, β-hexosaminidase. AbstractBackground: Signal transduction pathways mediated by various receptors expressed on mast cells are thought to be complex, and inhibitory signals that turn off activating signals are not known. Methods: Upstream signaling cascades mediated by several known receptors in bonemarrow-derived mast cells that lead to degranulation and mediator release were studied by immunoblotting and immunoprecipitation. Small interfering RNAs and knockout mice were used to confirm findings. Results: All ligands tested including IgE/Ag, SCF, HSP70, CCL3, and its valiant eMIP induced phosphorylation of linker for activation of T cells (LAT), which triggered their receptor-mediated downstream signaling cascades that controlled degranulation and mediator release. Phosphorylation of lymphocyte-specific protein kinase (Lck) was induced by each ligand, which commonly played an indispensable role in LAT phosphorylation. In contrast, phosphorylation of spleen tyrosine kinase was additionally induced in cells stimulated only with IgE/Ag and SCF, which is also associated with LAT phosphorylation in part. Degranulation and mediator release induced by IgE/Ag, SCF, or HSP70 were enhanced by nanomolar doses of CCR1 ligands CCL3 and eMIP via enhanced LAT phosphorylation. On the other hand, micromolar doses of CCR1 ligand inhibited degranulation and mediator release from mast cells stimulated with IgE/Ag, SCF, or HSP70 by de-phosphorylation of phosphorylated Lck with Src homology region 2 domain-containing phosphatase-1.

Antihistamines and azithromycin as a treatment for COVID-19 on primary health care – A retrospective observational study in elderly patients

“…Although this study is descriptive, our results bear some similarities with other studies [ 26 , 36 , 37 ]. Mast cells seem to play an important role in the inflammatory responses by releasing granules of histamine, in addition to synthesizing and secrete inflammatory lipid mediators and pro-inflammatory cytokines TNF-α and IL-6 [ 38 ]. The use of antihistamines may help to minimize the histamine-mediated cytokine storm [ 39 ].…”

Zika Virus Infects Human Placental Mast Cells and the HMC-1 Cell Line, and Triggers Degranulation, Cytokine Release and Ultrastructural Changes

“…Replication was inferred by the detection of the NS1 protein of Zika, which is a non-structural protein that is not a constituent of the virus particle and is only present after its synthesis at the time of replication [9]. It is known that mast cells have the requisite receptors, such as FcGR, HSP70 and others, that could mediate the entry of ZIKV, and also mediate the entry of other arboviruses like dengue, as well as being involved in the transduction signals for the degranulation cascade [21,34].…”

Análise Dos Fatores De Prevenção Do Câncer Ginecológico

“…Replication was inferred by the detection of the NS1 protein of Zika, which is a non-structural protein that is not a constituent of the virus particle and is only present after its synthesis at the time of replication [9]. It is known that mast cells have the requisite receptors, such as FcɣR, HSP70 and others, that could mediate the entry of ZIKV, which also mediate the entry of other arboviruses like dengue as well as being involved in the transduction signals for the degranulation cascade [21,34].…”