TRPV1 activation in human Langerhans cells and T cells inhibits mucosal HIV-1 infection via CGRP-dependent and independent mechanisms

Abstract

Upon its mucosal transmission, HIV type 1 (HIV-1) rapidly targets genital antigen-presenting Langerhans cells (LCs), which subsequently transfer infectious virus to CD4 + T cells. We previously described an inhibitory neuroimmune cross talk, whereby calcitonin gene-related peptide (CGRP), a neuropeptide secreted by peripheral pain-sensing nociceptor neurons innervating all mucosal epithelia and associating with LCs, strongly inhibits HIV-1 transfer. As nociceptors secret CGRP following the activation of their Ca 2+ ion channel transient receptor potential vanilloid 1 (TRPV1), and as we reported that LCs secret low levels of CGRP, we investigated whether LCs express functional TRPV1. We found that human LCs expressed mRNA and protein of TRPV1, which was functional and induced Ca 2+ influx following activation with TRPV1 agonists, including capsaicin (CP). The treatment of LCs with TRPV1 agonists also increased CGRP secretion, reaching its anti-HIV-1 inhibitory concentrations. Accordingly, CP pretreatment significantly inhibited LCs-mediated HIV-1 transfer to CD4 + T cells, which was abrogated by both TRPV1 and CGRP receptor antagonists. Like CGRP, CP-induced inhibition of HIV-1 transfer was mediated via increased CCL3 secretion and HIV-1 degradation. CP also inhibited direct CD4 + T cells HIV-1 infection, but in CGRP-independent manners. Finally, pretreatment of inner foreskin tissue explants with CP markedly increased CGRP and CCL3 secretion, and upon subsequent polarized exposure to HIV-1, inhibited an increase in LC–T cell conjugate formation and consequently T cell infection. Our results reveal that TRPV1 activation in human LCs and CD4 + T cells inhibits mucosal HIV-1 infection, via CGRP-dependent/independent mechanisms. Formulations containing TRPV1 agonists, already approved for pain relief, could hence be useful against HIV-1.

Anandamide modulation of monocyte-derived Langerhans cells: implications for immune homeostasis and skin inflammation

“…Although anandamide increased the intracellular calcium concentration of moLCs as determined by fluorescent calcium imaging, not all cells were equally responsive to anandamide ( Figure 3 , Supplementary Videos 1 - 4 ). In fact, the calcium transient that can be observed occurs relatively late after the application of anandamide (with an approximate maximal response at 150 seconds), which stands in contrast to the response elicited by capsaicin on a similar moLC model ( 33 ). According to the kinetics of the calcium response, and the low number of responsive cells, it is unlikely that the effects of anandamide are dependent on TRPV1 activation on our moLCs.…”

“…Specifically, CD14 + monocytes from adult peripheral blood undergo differentiation into monocyte-derived LCs (moLCs) when exposed to granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-4, and transforming growth factor β (TGF- β) ( 27 – 29 ). There is no standard protocol widely adopted among research groups for generating moLCs ( 27 , 30 – 33 ). Our research group worked to refine protocols to ensure the accuracy and reproducibility of the moLC experiments ( 34 ).…”

Interleukin-1α links peripheral CaV2.2 channel activation to rapid adaptive increases in heat sensitivity in skin

“…5 ). But intradermal capsaicin may also act on nonneuronal Trpv1 expressing cells in skin, including keratinocytes 79 T-cells 80 Langerhans cells 81 which may contribute to Ca V 2.2-independent sources of cytokines, including IL-1α. For example, capsaicin could act on immune cells directly, triggering the production and/or release of IL-1α independent of Ca V 2.2 channels and nociceptor activation.…”