Functional Role of Transient Receptor Potential Channels in Immune Cells and Epithelia

Abstract

Transient receptor potential (TRP) ion channels are widely expressed in several tissues throughout the mammalian organism. Originally, TRP channel physiology was focusing on its fundamental meaning in sensory neuronal function. Today, it is known that activation of several TRP ion channels in peptidergic neurons does not only result in neuropeptide release and consecutive neurogenic inflammation. Growing evidence demonstrates functional extra-neuronal TRP channel expression in immune and epithelial cells with important implications for mucosal immunology. TRP channels maintain intracellular calcium homeostasis to regulate various functions in the respective cells such as nociception, production and release of inflammatory mediators, phagocytosis, and cell migration. In this review, we provide an overview about TRP-mediated effects in immune and epithelial cells with an emphasis on mucosal immunology of the gut. Crosstalk between neurons, epithelial cells, and immune cells induced by activation of TRP channels orchestrates the immunologic response. Understanding of its molecular mechanisms paves the way to novel clinical approaches for the treatment of various inflammatory disorders including IBD.

Keywords: colitis; cytokines; macrophages; neurogenic inflammation; neuropeptides; nociception.

Figure 1

Crosstalk between neurons, immune cells, and epithelial cells controls colonic homeostasis. A vital interplay between neurons, immune cells, and epithelial cells is crucial for colonic homeostasis. Aberrant function of one or more of these players may cause inflammation. For instance, activated macrophages release IL-1ß which among other cytokines acts as a chemoattractant to human peripheral blood mononuclear cells (PBMCs) (45). On the other hand, IL-1ß increases TNF-α receptor expression in epithelial cells which may promote TNF-α-mediated inflammatory responses and subsequently colitis. Moreover, IL-1ß acts on peptidergic sensory neurons through induction of pro-inflammatory substance P (SP) release. SP in turn induces migration of polymorphonuclear leukocytes in vivo (46). In addition, epithelial IL-8 and KC induce immune cell infiltration into the colonic wall. IL-10 is an essential immunoregulatory cytokine (47). Epithelial cells from murine small intestine and colon express the IL-10 receptor and its stimulation blocks IFN-γ-mediated pro-inflammatory effects (48). Moreover, not only epithelial cells but also enteric neurons express cytokines and chemokines such as IL-8, whose neuronal production is promoted by IL-1ß via MAPK signaling pathways (49).