MYC-mediated silencing of miR-181a-5p promotes pathogenic Th17 responses by modulating AKT3-FOXO3 signaling

Chen, Sisi; Ma, Binyun; Li, Xue; Zhang, Kailang; Wei, Yankai; Du, Bei; Liu, Xun; Wei, Ruihua; Li, Xiaorong; Nian, Hong

doi:10.1016/j.isci.2022.105176

Cited by 6 publications

(9 citation statements)

References 56 publications

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“…We supposed that lactylation mainly affected T H 17 function under current conditions and that T H 17 cells played vital roles in modulating EAU development. As previously reported, adoptively transferring IRBP-immunized T H 17-specific cells into naïve mice can induce EAU, and suppressing T H 17 function alone could efficiently inhibit EAU progression ( 2 , 36 , 37 ).…”

Section: Resultssupporting

confidence: 61%

Global lactylome reveals lactylation-dependent mechanisms underlying T _H 17 differentiation in experimental autoimmune uveitis

Fan,

Wang,

Zeng

et al. 2023

Sci. Adv.

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Dysregulation of CD4 + T cell differentiation is linked to autoimmune diseases. Metabolic reprogramming from oxidative phosphorylation to glycolysis and accumulation of lactate are involved in this process. However, the underlying mechanisms remain unclear. Our study showed that lactate-derived lactylation regulated CD4 + T cell differentiation. Lactylation levels in CD4 + T cells increased with the progression of experimental autoimmune uveitis (EAU). Inhibition of lactylation suppressed T H 17 differentiation and attenuated EAU inflammation. The global lactylome revealed the landscape of lactylated sites and proteins in the CD4 + T cells of normal and EAU mice. Specifically, hyperlactylation of Ikzf1 at Lys 164 promoted T H 17 differentiation by directly modulating the expression of T H 17-related genes, including Runx1, Tlr4, interleukin-2 (IL-2), and IL-4. Delactylation of Ikzf1 at Lys 164 impaired T H 17 differentiation. These findings exemplify how glycolysis regulates the site specificity of protein lactylation to promote T H 17 differentiation and implicate Ikzf1 lactylation as a potential therapeutic target for autoimmune diseases.

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Section: Resultssupporting

confidence: 61%

Global lactylome reveals lactylation-dependent mechanisms underlying T _H 17 differentiation in experimental autoimmune uveitis

Fan,

Wang,

Zeng

et al. 2023

Sci. Adv.

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“…6A). Combined with the miRNA microarray data of EAU CD4 + T cells shown in our previous study [12], miR-128-3p was found to be the most downregulated in EAU CD4 + T cells (Fig. 6B).…”

Section: Neat1 Inhibits the Transcriptional Activity Of Nono To Incre...supporting

confidence: 68%

LncRNA Neat1 targets NonO and miR-128-3p to promote antigen-specific Th17 cell responses and autoimmune inflammation

Chen,

Wang,

Zhang

et al. 2023

Cell Death Dis

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Long non-coding RNAs (lncRNAs) interaction with RNA-Binding proteins (RBPs) plays an important role in immunological processes. The generation of antigen-specific Th17 cells is closely associated with autoimmune pathogenesis. However, the function of lncRNA-RBP interactions in the regulation of pathogenic Th17 cell responses during autoimmunity remains poorly understood. Here, we found that lncRNA Neat1, highly expressed in Th17 cells, promoted antigen-specific Th17 cell responses. Both global and CD4+ T cell-specific knockdown of Neat1 protected mice against the development of experimental autoimmune uveitis (EAU). Mechanistically, Neat1 regulated RNA-Binding protein NonO, thus relieving IL-17 and IL-23R from NonO-mediated transcriptional repression and supporting antigen-specific Th17 cell responses. In addition, Neat1 also modulated miR-128-3p/NFAT5 axis to increase the expression of IL-17 and IL-23R, leading to augmented Th17 cell responses. Our findings elucidate a previously unrecognized mechanistic insight into the action of Neat1 in promoting antigen-specific Th17 responses and autoimmunity, and may facilitate the development of therapeutic targets for T cell-mediated autoimmune diseases.

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“…3.2 | miR-338-3p in DCs positively regulated pathogenic Th17 response in vitro IRBP 1-20 -specific Th17 cells are central to the pathogenesis of EAU. 37,38 Given that levels of Th17-polarizing cytokines IL-6, IL-1β, and IL-23 are increased in miR-338-3p-overexpressing DCs, we next explore whether miR-338-3p in DCs could affect IRBP 1-20 -specific Th17 cell responses. For this, DCs infected with LV-miR-338 or LV-Ctrl were pulsed with IRBP 1-20 and co-cultured with T cells from EAU mice under Th17-polarizing conditions.…”

Section: Resultsmentioning

confidence: 99%

“…IRBP 1–20 ‐specific Th17 cells are central to the pathogenesis of EAU 37,38 . Given that levels of Th17‐polarizing cytokines IL‐6, IL‐1β, and IL‐23 are increased in miR‐338‐3p‐overexpressing DCs, we next explore whether miR‐338‐3p in DCs could affect IRBP 1–20 ‐specific Th17 cell responses.…”

Section: Resultsmentioning

confidence: 99%

Mettl3 induced miR‐338‐3p expression in dendritic cells promotes antigen‐specific Th17 cell response via regulation of Dusp16

Wei,

Yang,

Liu

et al. 2023

The FASEB Journal

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Pathogenic Th17 cells are critical drivers of multiple autoimmune diseases, including uveitis and its animal model, experimental autoimmune uveitis (EAU). However, how innate immune signals modulate pathogenic Th17 responses remains largely unknown. Here, we showed that miR‐338‐3p endowed dendritic cells (DCs) with an increased ability to activate interphotoreceptor retinoid‐binding protein (IRBP)1–20‐specific Th17 cells by promoting the production of IL‐6, IL‐1β, and IL‐23. In vivo administration of LV‐miR‐338‐infected DCs promoted pathogenic Th17 responses and exacerbated EAU development. Mechanistically, dual‐specificity phosphatase 16 (Dusp16) was a molecular target of miR‐338‐3p. miR‐338‐3p repressed Dusp16 and therefore strengthened the mitogen‐activated protein kinase (MAPK) p38 signaling, resulting in increased production of Th17‐polarizing cytokines and subsequent pathogenic Th17 responses. In addition, methyltransferase like 3 (Mettl3), a key m6A methyltransferase, mediated the upregulation of miR‐338‐3p in activated DCs. Together, our findings identify a vital role for Mettl3/miR‐338‐3p/Dusp16/p38 signaling in DCs‐driven pathogenic Th17 responses and suggest a potential therapeutic avenue for uveitis and other Th17 cell‐related autoimmune disorders.

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MYC-mediated silencing of miR-181a-5p promotes pathogenic Th17 responses by modulating AKT3-FOXO3 signaling

Cited by 6 publications

References 56 publications

Global lactylome reveals lactylation-dependent mechanisms underlying T _H 17 differentiation in experimental autoimmune uveitis

Global lactylome reveals lactylation-dependent mechanisms underlying T _H 17 differentiation in experimental autoimmune uveitis

LncRNA Neat1 targets NonO and miR-128-3p to promote antigen-specific Th17 cell responses and autoimmune inflammation

Mettl3 induced miR‐338‐3p expression in dendritic cells promotes antigen‐specific Th17 cell response via regulation of Dusp16

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MYC-mediated silencing of miR-181a-5p promotes pathogenic Th17 responses by modulating AKT3-FOXO3 signaling

Cited by 6 publications

References 56 publications

Global lactylome reveals lactylation-dependent mechanisms underlying T H 17 differentiation in experimental autoimmune uveitis

Global lactylome reveals lactylation-dependent mechanisms underlying T H 17 differentiation in experimental autoimmune uveitis

LncRNA Neat1 targets NonO and miR-128-3p to promote antigen-specific Th17 cell responses and autoimmune inflammation

Mettl3 induced miR‐338‐3p expression in dendritic cells promotes antigen‐specific Th17 cell response via regulation of Dusp16

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Global lactylome reveals lactylation-dependent mechanisms underlying T _H 17 differentiation in experimental autoimmune uveitis

Global lactylome reveals lactylation-dependent mechanisms underlying T _H 17 differentiation in experimental autoimmune uveitis