Let-7f-5p suppresses Th17 differentiation via targeting STAT3 in multiple sclerosis

Abstract

T helper 17 (Th17) cells are regarded as key factors in the pathogenesis of multiple sclerosis (MS). Although the involvement of certain microRNAs (miRNAs) in the development of MS has been reported, their roles in Th17 cell differentiation and MS pathogenesis remain elusive. In this study, we identified that let-7f-5p expression is significantly downregulated in CD4 + T cells from MS patients and during the process of Th17 differentiation. The overexpression of let-7f-5p suppressed Th17 differentiation, whereas the knockdown of let-7f-5p expression enhanced this progress. We then explored the molecular mechanism through which let-7f-5p suppressed Th17 differentiation and identified signal transducer and activator of transcription 3 (STAT3), a pivotal transcription factor of Th17 cells, as a direct target of let-7f-5p. In contrast to the downregulated expression of let-7f-5p, STAT3 and p-STAT3 protein levels were dramatically upregulated and inversely correlated with let-7f-5p in peripheral blood CD4 + T cells from MS patients. In conclusion, let-7f-5p functions as a potential inhibitor of Th17 differentiation in the pathogenesis of MS by targeting STAT3 and may serve as a new therapeutic target.

RETRACTED: Mechanisms of M2 Macrophage-Derived Exosomal Long Non-coding RNA PVT1 in Regulating Th17 Cell Response in Experimental Autoimmune Encephalomyelitisa

“…STAT3 in CD41 and CD81 T cells was activated in the early stage of inflammatory diseases, reflecting proinflammatory response (43). STAT3 is an essential Th17 differentiation-specific protein, and is necessary for differentiation of CD4 + T cells to Th17 cell in EAE (44). Evidence has claimed that blockade of the JAK/STAT pathway was anticipated to offer therapeutic immunosuppression and anti-inflammation, and thus provide treatments for autoimmune diseases (45).…”

Circulating miRNA biomarkers for sporadic Amyotrophic Lateral Sclerosis: a systematic meta-analysis and empirical validation

“…Aberrant expression of let-7f has reported in several cancers. Previous studies also have provided evidence of decreasing expression of let-7f in multiple sclerosis (MS) and Alzheimer's diseases (AD) [39,40]. As presented in the systematic review, let-7f-5p expression was signi cantly downregulated in the peripheral blood, serum, plasma, and CSF of ALS patients [19,20,24,26,28].…”

“…Variation exists in the GU-rich sequences, but not in the seed sequence. Let-7f-5p is located in the intergenic region at 9q22.3 and is reported to involve in a series of physiological and pathological processes [39]. Aberrant expression of let-7f has reported in several cancers.…”

let7f‑5p attenuates inflammatory injury in in vitro pneumonia models by targeting MAPK6

“…The STAT3 signaling pathway is pivotal for the inflammatory response ( 31 ). In 2019, Li et al ( 36 ) reported that let7f-5p reduced Th17 differentiation in multiple sclerosis by targeting STAT3. In 2018, Kim et al ( 37 ) demonstrated that orientin repressed breast cancer cell invasion via the MAPK6/STAT3 signaling pathway ( 37 ).…”