The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression

Abstract

Summary T helper 17 (Th17) cells are key players in autoimmune diseases. However, the roles of non-coding RNAs in Th17 cell development and function are largely unknown. We found that deletion of the endoribonuclease Dicer1 gene specifically in Th17 cells protected mice from experimental autoimmune encephalomyelitis. We found that the Dicer1-regulated microRNA (miR)-183-96-182 cluster (miR-183C) was highly expressed in Th17 cells and was induced by cytokine IL-6-STAT3 signaling. miR-183C expression enhanced pathogenic cytokine production from Th17 cells during their development and promoted autoimmunity. Mechanistically, miR-183C in Th17 cells directly repressed expression of the transcription factor Foxo1. Foxo1 negatively regulated the pathogenicity of Th17 cells in part by inhibiting cytokine receptor IL-1R1 expression. These findings indicate that the miR-183C drives Th17 pathogenicity in autoimmune diseases via inhibition of Foxo1 and present promising therapeutic targets.

The miR-183/96/182 Cluster Regulates Macrophage Functions in Response to <b><i>Pseudomonas aeruginosa</i></b>

“…2-5) and organismic levels [13]. Target prediction analyses and experimental data from other organ systems have shown that miR-183/96/182 regulates hundreds of downstream target genes [7, 8, 18]; therefore, we predict that DAP12 and Nox2 are not the only functional targets of miR-183/96/182 in Mϕ and neutrophils to mediate its functions. We further predict that miR-183/96/182 may modulate other aspects of Mϕ and neutrophil functions, e.g., migration and chemotaxis, through targeting multiple genes involved in cytoskeletal reorganization [unpubl.…”

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

“…to B6 mice on the day of immunization. At 13 d postimmunization, uveitogenic T cells were isolated and restimulated with IRBP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and APCs under nonpolarizing conditions in the presence of Ag. As shown in Fig.…”

“…IL-23R signaling is required for the pathogenicity of Th17 cells in vivo (6,7). The development of pathogenic Th17 cells is orchestrated by a complex network of signaling pathways and transcriptional regulators in T cells (8,9). Although the involvement of T cell-intrinsic pathways has been studied extensively, how pathogenic Th17 development is shaped by extrinsic signals derived from the innate immune system is relatively less understood.…”

Structure-Function Relationships of CFTR in Health and Disease: The Pancreas Story

“…Many have suggested that the balance between Th1, Th2, and Th 17 could play a role in the CF disease (31). It has been established that Th17 is known to be a key player in autoimmune diseases (40). In addition, the authors showed that Th17 is regulated by miR-183C via inhibition of Foxo1 (40).…”

“…It has been established that Th17 is known to be a key player in autoimmune diseases (40). In addition, the authors showed that Th17 is regulated by miR-183C via inhibition of Foxo1 (40). For a long time, it has been thought that CFTR mutations in epithelia cells have an indirect effect on the immune system which causes the inflammation in the lungs, because of the colonization of bacteria in the lungs like P. aeruginosa, Burkholderia cenocepacia, and Mycobacterium abscessus which causes the infections in the CF patients (31).…”