Capsaicin, the spicy compound in chili peppers, has many know health advantages, for instance it can control inflammation, high cholesterol, obesity, cancer and hypertension. Capsaicin activates the ion channel Transient Receptor Potential Vanilloid 1 (TRPV1) that is expressed by a subset of sensory peripheral neurons called nociceptors. Such neurons are responsible for transmission of pain information to our brain, explaining why spicy foods elicit a burning sensation. In parallel, TRPV1 activation induces the release, from the free nociceptor endings that innervate all mucosal epithelia, of the vasodilator neuropeptide Calcitonin Gene-Related Peptide (CGRP), explaining why eating spicy foods also results in redness (i.e. CGRP induces dilation of blood vessels).
Nociceptors are the main source of CGRP, but not the only one: some non-neuronal cells, including cells of the immune system, can also secret CGRP. Previous studies performed by Yonatan GANOR (in the team of Mucosal Entry of HIV-1 and Mucosal Immunity), showed that Langerhans cells (LCs), the resident antigen presenting cells in mucosal tissues, secret CGRP. Unexpectedly, these studies also revealed that CGRP is endowed with important anti-viral activities. Accordingly, CGRP inhibits infection with human immunodeficiency virus type 1 (HIV-1), by preventing the transfer of infections virions, rapidly captured by LCs, to CD4+ T-cells that are the principal cellular targets of HIV-1.
In the current study directed by Yonatan Ganor and published in PNAS, the scientists wondered whether secretion of CGRP also involves activation of TRPV1 in LCs, alike that occurs in nociceptors. If so, could capsaicin prevent HIV-1 infection? This indeed turned out to be the case. The study first shows that human LCs, both those isolated from mucosal inner foreskin tissues (i.e. a genital site invaded by HIV-1) or differentiated in-vitro from blood monocytes express functional TRPV1 on their surface. Moreover, treatment of LC with capsaicin before pulsing with HIV-1 inhibits the formation of cell-cell conjugates between LCs and CD4+ T-cells, and the resulting transfer to and infection of CD4+ T-cells with HIV-1. Such inhibition is mediated by TRPV1 activation, as it is reverted in the presence of a TRPV1 inhibitor. Next, as the scientists speculated, the study reveals that capsaicin induces secretion from LCs of CGRP, which is partially responsible for inhibiting HIV-1.
Legend: Capsaicin (CP) inhibits HIV-1 infection of mucosal Langerhans cells (LCs) and CD4+ T-cells. (1) In LCs, HIV-1 binding to the LC-specific pathogen recognition lectin langerin induces viral internalization and subsequent degradation, while virions escaping degradation are transferred from LCs and infect CD4+ T-cells. Previous studies of the laboratory showed that CGRP activates its cognate receptor expressed by LCs and affects a multitude of cellular and molecular process (not shown), resulting in significant inhibition of LCs-to-T-cells mucosal HIV-1 transfer. (2) The present study shows that human LCs express functional TRPV1 on their surface. (3) Moreover, upon activation of TRPV1 by CP, LCs secret CGRP, which in turn is partially responsible for inhibition of HIV-1 transfer from LCs to CD4+ T-cells. (4) CP, but not CGRP, also inhibits the direct infection of CD4+ T-cell with HIV-1.
Finally, the scientists also tested the effects of CGRP and capsaicin on direct HIV-1 infection of CD4+ T-cells, in the absence of LCs. These experiments showed that capsaicin, but not CGRP, inhibits such direct infection, indicating that capsaicin acts in CD4+ T-cells in CGRP-independent manners (although T-cells are responsive to CGRP in other settings).
Activation of TRPV1 in nociceptors by capsaicin is followed by a long lasting refractory period with unresponsiveness to additional noxious stimuli (i.e. desensitization). Based on these observations, topical formulations containing capsaicin have been developed and already approved clinically as analgesics in painful conditions. The current study suggests that such formulations might be re-positioned now as original and novel neuroimmune strategies for prevention of mucosal HIV-1 transmission.
This study was funded by SIDACTION.
Reference
Jammy Mariotton , Emmanuel Cohen, Aiwei Zhu, Cédric Auffray, Caio César Barbosa Bomfim, Nicolas Barry Delongchamps, Marc Zerbib , Morgane Bomsel, Yonatan Ganor Y. TRPV1 activation in human Langerhans cells and T-cells inhibits mucosal HIV-1 infection via CGRP-dependent and independent mechanisms. Proc Natl Acad Sci U S A. 2023, May 30;120(22):e2302509120. doi: 10.1073/pnas.2302509120. Epub 2023 May 22. PMID: 37216549.
