A study published in Nature Immunology reveals a previously unrecognized, ‘non-canonical’ role of the pain TRPV1 receptor – namely, its functional expression, and involvement in TCR signaling and pro-inflammatory activities of T cells.
Transient receptor potential vanilloid type 1 ion channel (TRPV1), initially identified as the receptor for capsaicin (the hot ingredient of chilli peppers) belongs to the family of nociceptors (pain receptors).
It is mostly expressed in sensory neurons and responds to noxious stimuli such as heat (>42 C°), protons and vanilloids such as capsaicin or allyl isothiocyanate, the pungent compound in mustard and wasabi. TRPV1 also contributes to the development of burning pain and reflex hyperactivity associated with inflammation of peripheral tissues and viscera (Nagy I et al., Prog Drug Res, 2014, 68:39).
In the Nature Immunology study, Samuel Bertin and colleagues, as part of an international research team from the US, Japan, Canada and China found that the TRPV1 was constitutively expressed in mouse and human CD4+ T cells, and the Jurkat human leukemic T cell line.
The whole-cell patch clamp demonstrated the functionality of the TRPV1 channel at the plasma membrane, recording capsaicin-induced currents in CD4+ T cells.
The authors provided evidence that TRPV1 is a functional Ca2+channel, contributing to TCR-induced Ca2+ influx. Importantly, they showed that it was necessary for proper downstream TCR-induced signaling and cytokine production, such as IFN-γ, IL-17A and TNF, and the T cell inflammatory responses in vivo in two models of inflammatory bowel disease.
In addition, the authors demonstrated that TRPV1 antagonists expressed immune-modulatory properties; they suggest that their application may prove beneficial in immune- and T cell-related diseases such as inflammatory bowel disease.
A 2017 review summarizes the role of TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation, and the pro-inflammatory response induced by their activation. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) are known to specifically participate in pain and cutaneous neurogenic inflammation (CNI).
Particularly TRPV1 is a nociceptive cationic (mainly Ca2+) channel responsive to high temperature (>43°C), and it can be activated by the natural agonist capsaicin. High temperature and capsaicin have been demonstrated to activate sensory nerves and induce neurogenic inflammation.
Exposure of keratinocytes to capsaicin or UV radiation leads to TRPV1-mediated Ca2+ influx, followed by the increased expression of cyclooxygenase (COX)-2, IL-1β, IL-2, IL-4, and IL-8, tumor necrosis factor (TNF)-α, PGE2, and LTB4, as well as several MMPs.
TRPV1 activation by capsaicin evokes Ca2+ elevation in numerous mast cell lines. Thus, capsaicin-elicited Ca2+ did not induce mast cell degranulation but triggered the release of IL-4. TRPV1 is also expressed in endothelial cells and smooth muscle cells, and its activation induces vasorelaxation by releasing nitric oxide (NO) by a Ca2+ influx-dependent mechanism.
Olivier Gouin et al. concluded that TRPV1 is the mediator of the cross-talk between sensory nerve endings, skin non-immune and immune cells, which results in the release of inflammatory mediators such as cytokines and neuropeptides. These mediators act directly via specific receptors on neighboring cells, and, thus, TRPV1 mediates the neurogenic inflammation.
A 2019 review discusses the role of TRPV1 as a bridge between inflammation, cancer and immunity. The authors point out that the expression of TRPV1 was demonstrated in several tumor types including human breast cancer cell lines, human papillary thyroid carcinoma, prostate cancer, urothelial cancer cells, and glioma.
TRPV1 expression was upregulated in the several native breast cancers, but downregulation of TRPV1 expression was associated with progression of urothelial cancer. Thus, the exact role of TRPV1 in tumorigenesis is not clear. TRPV1 is sensitized by inflammatory mediators and its activation can lead to the release of calcitonin gene-related peptide (CGRP) and substance P, known proinflammatory factors.
A 2022 reviewoutlines TRPV1 as a novel regulator of the immune system. It is well known that temperature changes, including fever boost protective immune responses. Interestingly, TRPV1 may represent an important regulator of physiological body temperature and fever, outside the central nervous system. And TRPV1 may function as a temperature sensor in CD4+ T cells (see Figure 1).
Figure 1. Fever determines the fate of CD4+ T cells. Febrile temperature changes enhance Th2 differentiation and reduce Th1 differentiation via a TRPV1-regulated Notch-dependent pathway. In addition, febrile temperature promotes Th17 cell differentiation which depends on HSP-70- and HSP-90-related heat shock response and enhances SUMOylation of SMAD4 transcription factor at its K113 and K159 residues. HSP90, heat shock proteins 90; HSP70, heat shock proteins 70. From ‘Transient Receptor Potential Vanilloid1 (TRPV1) Channel Opens Sesame of T Cell Responses and T Cell-Mediated Inflammatory Diseases’ Front. Immunol., 11 May 2022, by Tengfei Xiao, Mingzhong Sun, Jingjing Kang and Chuanxiang Zhao. Public Domain.
In conclusion, the authors discusss that TRPV1 is a Ca2+-permeable channel and mediates TCR-induced Ca2+ influx, leading to T cell activation and death as well as differentiation of T cell subsets. Generally, TRPV1 regulates T cell-mediated inflammation and protect the body by regulating production of T cell-related cytokines, such as TNF-α, IL-4 and IL-6. However, due to diverse expression on sensory nerves, immune cells, and other cells, and the release of other inflammatory mediators, the overall functions of TRPV1 in inflammatory diseases need further evaluation.