Abstract
Transient Receptor Potential Ankyrin 1 (TRPA1) has been reported to influence neuroinflammation and lymphocyte function. We analysed the immune phenotype and activation characteristics of TRPA1-deficient mice (knockout—KO) generated by targeted deletion of the pore-loop domain of the ion channel. We compared TRPA1 mRNA and protein expression in monocyte and lymphocyte subpopulations isolated from primary and secondary lymphatic organs of wild type (WT) and KO mice. qRT-PCR and flow cytometric studies indicated a higher level of TRPA1 in monocytes than in lymphocytes, but both were orders of magnitude lower than in sensory neurons. We found lower CD4+/CD8+ thymocyte ratios, diminished CD4/CD8 rates, and B cell numbers in the KO mice. Early activation marker CD69 was lower in CD4+ T cells of KO, while the level of CD8+/CD25+ cells was higher. In vitro TcR-mediated activation did not result in significant differences in CD69 level between WT and KO splenocytes, but lower cytokine (IL-1β, IL-6, TNF-α, IL-17A, IL-22, and RANTES) secretion was observed in KO splenocytes. Basal intracellular Ca2+ level and TcR-induced Ca2+ signal in T lymphocytes did not differ significantly, but interestingly, imiquimod-induced Ca2+ level in KO thymocytes was higher. Our results support the role of TRPA1 in the regulation of activation, cytokine production, and T and B lymphocytes composition in mice.
Highlights
Emerging evidence indicates that Transient Receptor Potential Ankyrin 1 (TRPA1) is a molecular ionotropic receptor mediator [1] of the neuro-immuno-epithelial interface network [2,3,4] in the lung [5], skin [6]and gut [3,7,8] acting as a “pro-inflammatory hub” [9,10,11]
Dysfunction or inhibition of TRPA1 has been shown to decrease inflammation- related symptoms of psoriasis [6,12,13], rheumatoid arthritis [14], actinic keratosis [15], atopic dermatitis [16,17,18], multiple sclerosis [19,20,21,22,23,24], and its function has been proposed to contribute to a variety of interrelated sensory and inflammatory processes such as inflammatory hyperalgesia [25,26], colitis [7,27], airway inflammation [28,29] and even oxidative stress storm syndromes in COVID-19 [30,31]
Genetic disruption and pharmacological blockade of TRPA1 activity indicated that TRPA1 can be considered as part of a regulatory loop, an excitatory ion channel in primary sensory neurons in the peripheral nervous system, in keratinocytes and other non-neuronal cells, triggering the release of pro-inflammatory and inflammatory mediators such as calcitonin gene related peptide (CGRP), substance P (SP), IL-1β, IL-6 and IL-8 [34,35,36,37] TRPA1 is responsive to a subset of inflammatory mediators such as bradykinins, histamines, eicosanoid, and prostaglandins [33,38,39] that activate inflammatory signaling pathways such as phosphoinositide-dependent phospholipase C (PLC-β) signaling with formation of inositol 1,4,5-triphosphate (IP3) and Ca2+ mobilization from intracellular stores and subsequent activation of either PI3K/NF-κB pathway or the ASK1/p38 pathway and subsequently CREB, or by cAMP signaling pathway through adenylate cyclase [40,41,42]
Summary
Emerging evidence indicates that TRPA1 is a molecular ionotropic receptor mediator [1] of the neuro-immuno-epithelial interface network [2,3,4] in the lung [5], skin [6]and gut [3,7,8] acting as a “pro-inflammatory hub” [9,10,11]. Dysfunction or inhibition of TRPA1 has been shown to decrease inflammation- related symptoms of psoriasis [6,12,13], rheumatoid arthritis [14], actinic keratosis [15], atopic dermatitis [16,17,18], multiple sclerosis [19,20,21,22,23,24], and its function has been proposed to contribute to a variety of interrelated sensory and inflammatory processes such as inflammatory hyperalgesia [25,26], colitis [7,27], airway inflammation [28,29] and even oxidative stress storm syndromes in COVID-19 [30,31]. Pharmaceuticals 2022, 15, 57 stress such as nitric oxide, hydrogen peroxide, and inflammatory signals [1,9,10,11,32,33].
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