ABSTRACT
Mechanical forces can modulate the immune response, mostly described as promoting the activation of immune cells, but the role and mechanism of pathological levels of mechanical stress in lymphocyte activation have not been focused on before. By an ex vivo experimental approach, we observed that mechanical stressing of murine spleen lymphocytes with 50 mmHg for 3 h induced the nuclear localization of NFAT1, increased C-Jun, and increased the expression of early activation marker CD69 in resting CD8+ cells. Interestingly, 50 mmHg mechanical stressing induced the nuclear localization of NFAT1; but conversely decreased C-Jun and inhibited the expression of CD69 in lymphocytes under lipopolysaccharide or phorbol 12-myristate 13-acetate/ionomycin stimulation. Additionally, we observed similar changes trends when comparing RNA-seq data of hypertensive and normotensive COVID-19 patients. Our results indicate a biphasic effect of mechanical stress on lymphocyte activation, which provides insight into the variety of immune responses in pathologies involving elevated mechanical stress.
Subject(s)
Lymphocyte Activation/immunology , Stress, Mechanical , Animals , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Biomarkers/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , COVID-19/complications , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Comorbidity , Gene Expression Regulation/drug effects , Humans , Hypertension/complications , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Ion Channels/metabolism , Lectins, C-Type/metabolism , Lipopolysaccharides/pharmacology , Lymphocyte Activation/drug effects , Lymphocyte Activation/genetics , Male , Mice, Inbred C57BL , NFATC Transcription Factors/metabolism , Protein Transport/drug effects , Proto-Oncogene Proteins c-jun/metabolism , Signal Transduction/drug effects , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
Thymic stromal lymphopoietin (TSLP) produced by mast cells is involved in allergic inflammation pathogenesis. Chloroquine (CQ) is known to be an anti-malarial drug; however, additional protective functions of CQ have been discovered. This study aims to clarify an anti-inflammatory effect of CQ through modulating TSLP levels using an in vitro model of phorbol myristate acetate (PMA) + A23187-activated human mast cell line (HMC-1) and an in vivo model of PMA-irritated ear edema. CQ treatment reduced the production and mRNA expression levels of TSLP in activated HMC-1 cells. CQ down-regulated caspase-1 (CASP1), MAPKs, and NF-κB levels enhanced by stimulation with PMA + A23187. Moreover, ear thickness in ear edema was suppressed following CQ treatment. CQ decreased CASP1 and NF-κB levels in the ear tissue. TSLP levels in the ear tissue and serum were reduced following CQ treatment. Collectively, the above findings elucidate that CQ inhibits the pro-inflammatory mechanisms of TSLP via the down-regulation of distinct intracellular signaling cascade in mast cells. Therefore, CQ may have protective roles against TSLP-mediated inflammatory disorders.