microRNA-142–mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance

Abstract

Tregs play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). This function is dependent on maintenance of a high intracellular cAMP concentration. A number of microRNAs are implicated in the maintenance of Tregs. In this study, we demonstrate that peripheral immune tolerance is critically dependent on posttranscriptional repression of the cAMP-hydrolyzing enzyme phosphodiesterase-3b ( Pde3b ) by microRNA-142-5p (miR-142-5p). In this manner, miR-142-5p acts as an immunometabolic regulator of intracellular cAMP, controlling Treg suppressive function. Mir142 was associated with a super enhancer bound by the Treg lineage–determining transcription factor forkhead box P3 (FOXP3), and Treg-specific deletion of miR-142 in mice (Treg Δ142 ) resulted in spontaneous, lethal, multisystem autoimmunity, despite preserved numbers of phenotypically normal Tregs. Pharmacological inhibition and genetic ablation of PDE3B prevented autoimmune disease and reversed the impaired suppressive function of Tregs in Treg Δ142 animals. These findings reveal a critical molecular switch, specifying Treg function through the modulation of a highly conserved, cell-intrinsic metabolic pathway. Modulation of this pathway has direct relevance to the pathogenesis and treatment of autoimmunity and cancer.

miR‐142‐5p protects against osteoarthritis through competing with lncRNA XIST

“…Previously, miR-142-5p was found to be tumor-suppressing in lung adenocarcinoma, 28 pancreatic cancer 29 and gastric cancer, 30 and was reported to be cisplatin-related in ovarian cancer. 31 Additionally, miR-142-5p is associated with peripheral immune tolerance, 32 as well as a profibrogenic macrophage program. 33 In the present study, we revealed that miR-142-5p suppresses chondrocyte apoptosis and promotes proliferation.…”

Non-Coding RNAs in CD4+ T Cells: New Insights Into the Pathogenesis of Systemic Lupus Erythematosus

“…Interestingly, miR-142-5p, another mature isoform of miR-142, plays a positive role in regulating cAMP-mediated suppressor function of Treg cells. Deleting miR-142-5p decreases the concentration of intracellular cAMP by targeting AMPhydrolyzing enzyme phosphodiesterase-3b (Pde3b), leading to the deficient function of Treg cells and immune disorder in mice despite preserving a number of Treg cells with a normal phenotype(89). miR-99a and miR-150 can target mTOR, which is responsible for cell growth, to promote the differentiation of Treg cells at the expense of inhibiting Th17 cells(90).…”

Involvement of miR-142 and miR-155 in Non-Infectious Complications of CVID

“…Paradoxically, the overexpression of miR-142-5p targeting Smad3 has been shown to lead to cancer progression through the suppression of TGF-β-induced growth inhibition in cancer cells [ 10 ]. miR-142-5p is the predominant isoform expressed in thymically derived Tregs and determines peripheral immune tolerance suppressing self-reactive peripheral T effector cell (Teff) responses, thus limiting the development of autoimmunity activity and the upregulation of PDE3B, causing reduced intracellular cAMP and a failure of peripheral tolerance [ 13 ].…”

“…For example, miR-155 upregulates the production of Tregs through the SOCS1. First, Anandagoda reported that miR-142 plays a cell-intrinsic positive role in reinforcing Treg repressive activity [ 13 ]. Previously, Huang et al demonstrated that Teff maintains high levels of the other isoform –3p to limit adenylyl cyclase 9 (AC9) expression, an enzyme fundamental for cAMP production in CD4 + Tcells, thus restricting endogenous cAMP generation.…”