Sirtuin6 inhibits c-triggered inflammation through TLR4 abrogation regulated by ROS and TRPV1/CGRP.

Abstract

Propionibacterium acnes induces inflammatory and plays a vital role in the formation of comedones through activation of inflammatory cells, keratinocytes, and sebocytes. Sirtuin6 (SIRT6), along with ADP-ribosyltransferase and deacetylase, has been proposed to mediate various biological functions, including inflammation. Nevertheless, no strong experimental evidence has been provided to support the effect of SIRT6 in treatment of inflammatory situation. Therefore, this study addressed the inhibitory effect of SIRT6 against P. acnes-triggered inflammation in human keratinocytes and monocyte cell lines. In our study, proinflammation capacity of P. acnes was confirmed by increased levels of various inflammatory modulators, such as interleukin (IL)-1β, IL-6, IL-12, monocyte chemoattractant protein-1, interferon-γ, and tumor necrosis facto-α, both in vivo and in vitro. P. acnes stimulation also decreased SIRT6 expression, whereas, SIRT6 overexpression successfully suppressed the production of these cytokines in P. acnes-infected cells, and therefore controlled inflammation. Furthermore, we found that challenge of P. acnes stimulated the expression of toll-like receptor 4 (TLR4) in both cell lines. Nevertheless, SIRT6 overexpression attenuated the expression of TLR4 and consequently inhibited the P. acnes-triggered phosphorylation of nuclear transcription factor-kappa B (NF-κB) subunit, p65. Moreover, deactivation of TLR4 signaling pathway by SIRT6 overexpression resulted in significant downregulation of the transient receptor potential vanilloid (TRPV) pathway, cAMP response element-binding protein (CREB)/calcitonin gene-related peptide (CGRP) signaling, and NF-κB-regulated production of reactive oxygen species. These results indicate that SIRT6 serves as a potential therapeutic target to alleviate acne inflammation.