MiR-146a modulates TLR1/2 and 4 induced inflammation and links it with proliferation and lipid production via the indirect regulation of GNG7 in human SZ95 sebocytes

Katalin Dull,Christos C Zouboulis,Dóra Kovács,Andrea Szegedi,Dávid Deák,Fruzsina Fazekas,Dániel Törőcsik,Szilárd Póliska

doi:10.1038/s41598-021-00907-1

Katalin Dull, Christos C Zouboulis + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-00907-1

Copy DOI

Abstract

Activation of Toll-like receptors (TLR) 1/2 and 4 are central in inducing inflammation in sebocytes by regulating the expression of protein coding mRNAs, however the microRNA (miRNA) profile in response to TLR activation and thus the possible role of miRNAs in modulating sebocyte functions has not been elucidated. In this work we identified miR-146a to have the highest induction in the TLR1/2 and 4 activated SZ95 sebocytes and found that its increased levels led to the down-regulation of IL-8 secretion, decreased the chemoattractant potential and stimulated the proliferation of sebocytes. Assessing the gene expression profile of SZ95 sebocytes treated with a miR-146a inhibitor, the induction of GNG7 was one of the highest, while when cells were treated with a miR-146a mimic, the expression of GNG7 was down-regulated. These findings correlated with our in situ hybridization results, that compared with control, miR-146a showed an increased, while GNG7 a decreased expression in sebaceous glands of acne samples. Further studies revealed, that when inhibiting the levels of GNG7 in SZ95 sebocytes, cells increased their lipid content and decreased their proliferation. Our findings suggest, that miR-146a could be a potential player in acne pathogenesis by regulating inflammation, inducing proliferation and, through the indirect down-regulation of GNG7, promoting the lipid production of sebocytes.

Highlights

Activation of Toll-like receptors (TLR) 1/2 and 4 are central in inducing inflammation in sebocytes by regulating the expression of protein coding mRNAs, the microRNA profile in response to TLR activation and the possible role of miRNAs in modulating sebocyte functions has not been elucidated
That G protein gamma 7 (GNG7) was found to be oppositely regulated both in SZ95 sebocytes as well as in sebaceous glands of acne samples, suggests a cascade of events in which the induction of miR-146a leads to proliferation, the consecutive down-regulation of GNG7 promotes lipid production of sebocytes
In line with our previous results, showing that TLR1/2 and TLR4 pathways induced a similar change in the mRNA profile of sebocytes, miRNAs changed in response to the used activating agents

Summary

Introduction

Activation of Toll-like receptors (TLR) 1/2 and 4 are central in inducing inflammation in sebocytes by regulating the expression of protein coding mRNAs, the microRNA (miRNA) profile in response to TLR activation and the possible role of miRNAs in modulating sebocyte functions has not been elucidated. Shaping the inflammatory e nvironment[19,20,21], in which their activation through T LRs14,22,23 might play a central role Supporting this pustulate, our previous genome wide gene expression study showed that sebocytes are able to rapidly gain and prioritize an immune-competent status in response to TLR1/2 and/or TLR4 activation at the level of mRNA e xpression[22]. Using whole tissue samples, miRNAs were linked to sebaceous gland associated tumors[26,27,28,29], the cellular source of the differentially expressed miRNAs was not assessed

Objectives

Methods

Results

Conclusion