miR-146a Inhibits Biofilm-Derived Cutibacterium acnes–Induced Inflammatory Reactions in Human Keratinocytes

Abstract

Acne is a chronic inflammatory skin disorder that often involves the formation of Cutibacterium acnes (C. acnes) biofilms. Several microRNAs (miRNAs) are known to be involved in inflammatory responses. However, it is unknown whether miRNAs play a role in the inflammatory reaction triggered by C. acnes biofilm. In this study, we investigated the role of miR-146a in biofilm-derived C. acneseinduced inflammatory responses. Increased expressions of miR-146a and toll-like receptor (TLR) 2 were detected in acne lesions. In the presence of biofilm-derived C. acnes, TLR2 and its downstream NF-kB and MAPK pathways were activated in keratinocytes. Subsequently, miR-146a was upregulated in these cells along with the induction of IL-6, IL-8, and tumor necrosis factor (TNF)-a. Furthermore, our data indicates that miR-146a could directly bind the 3 0-untranslated region of IRAK1 and TNF receptor-associated factor 6 (TRAF6) and suppress their expression, leading to an inhibition of biofilm-derived C. acneseinduced activation of NF-kB, p38, and ERK1/2 pathways. Overall, our results indicate that biofilm-derived C. acnes induces miR-146a, which can downregulate the production of IL-6,-8, and TNF-a in acne inflammation by inhibiting the TLR2/IRAK1/TRAF6/NF-kB and MAPK pathways.

A Janus-Faced Bacterium: Host-Beneficial and -Detrimental Roles of Cutibacterium acnes

“…Less well-understood is which C. acnes components, e.g., genomic DNA, surface/secreted proteins, peptidoglycan and cell wall polysaccharide, are actually sensed and how the pro-inflammatory activity of C. acnes is controlled/dampened on normal skin. C. acnes-exposed keratinocytes may attenuate TLR-induced inflammation by negative regulatory circuits involving proteins such as TNIP1 and TNFAIP3 and microRNAs such as miR-146a, that can downregulate the production of inflammatory cytokines and chemokines (Erdei et al, 2018(Erdei et al, , 2021Zeng et al, 2019). In addition, besides keeping bacteria in physical distance to immunocompetent cells, e.g., within infundibula of sebaceous follicles, another strategy to limited responses might be to eliminate invasive C. acnes.…”

miR-146a regulates TLR1/2 and 4 induced inflammation and links it with proliferation in human SZ95 sebocytes

“…In psoriasis, its genetic alterations even showed an association with disease severity [28][29][30] . Importantly, higher levels of miR-146a was also detected in keratinocytes of acne samples, where it may down-regulate P. acnesinduced production of IL-6, -8, and TNF-α by inhibiting the TLR2/IRAK1/TRAF6/NF-κB and MAPK pathways 31 . Our ndings that miR-146a was also highly expressed in sebaceous glands of acne samples, con rms that miR-146a may be involved in acne also at the level of sebocytes and adds further important details on the immune-competence of this cell type.…”

MicroRNA-490-3p inhibits inflammatory responses in LPS-induced acute lung injury of neonatal rats by suppressing the IRAK1/TRAF6 pathway

“…IRAK1, as a key molecule in the TLR4 signaling pathway, is also regulated by miRNAs. For example, miR-146a was revealed to bind to the 3'-UTR of IRAK1 and TRAF6, which attenuated their expression, thereby restricting activation of the inflammatory proteins including NF-κB, p38 and ERK1/2 (43). Overexpressing miR-146 reduced IRAK-1 and TRAF6 expression levels, thereby attenuating the inflammatory factors released, and attenuating LPS-induced ALI (44).…”