A microRNA upregulated in asthma airway T cells promotes TH2 cytokine production

Abstract

MicroRNAs (miRNAs) exert powerful effects on immune function by tuning networks of target genes that orchestrate cell behavior. We sought to uncover miRNAs and miRNA-regulated pathways that control the TH2 responses that drive pathogenic inflammation in asthma. Profiling miRNA expression in human airway-infiltrating T cells revealed miR-19a elevation in asthma. Modulating miR-19 activity altered TH2 cytokine production in both human and mouse T cells, and TH2 cell responses were markedly impaired in cells lacking the entire miR-17∼92 cluster. miR-19 promotes TH2 cytokine production and amplifies PI(3)K, JAK-STAT, and NF-κB signaling by direct targeting of PTEN, SOCS1, and A20. Thus, miR-19a up regulation in asthma may be an indicator and a cause of increased TH2 cytokine production in the airways.

MicroRNA regulation of lymphocyte tolerance and autoimmunity

“…PTEN has proven to be a multipotent miRNA target, having effects in many different immune cell types (18,(29)(30)(31)(32). A subset of mature B cells implicated in CLL progression expresses increased miR-22, which targets PTEN, leading to increased PI3K activity and proliferation (33).…”

Cross‐regulation between cytokine and microRNA pathways in T cells

“…In a recent study, Ansel and colleagues described the effect of the miR-17ß92 cluster, particularly miR-19a, in the control of Th2-type responses. Their initial observation was that miR-19a, and not other members of the same cluster, is overexpressed in T cells isolated from the airway of asthmatic individuals when compared with those of healthy donors [73]. The authors showed that miR-17ß92-deficient CD4 + T cells produce less IL-13, IL-5, and IL-4 and more tumor-necrosis factor, a known direct target of miR-19 [73, 74].…”

“…The authors showed that miR-17ß92-deficient CD4 + T cells produce less IL-13, IL-5, and IL-4 and more tumor-necrosis factor, a known direct target of miR-19 [73,74]. Mechanistically, miR-19 was shown to promote Th2 cytokine production and amplify inflammatory signaling by direct targeting of the inositol phosphatase PTEN, the signaling inhibitor SOCS1 and the deubiquitinase A20 [73]. All these miRNAs (listed in Table 1) could potentially constitute the basis of miRNA-based therapy of Th2-related pathologies, such as allergic airway inflammation, due to the accessible nature of the airways in the context of drug delivery.…”

“…Their initial observation was that miR-19a, and not other members of the same cluster, is overexpressed in T cells isolated from the airway of asthmatic individuals when compared with those of healthy donors [73]. The authors showed that miR-17ß92-deficient CD4 + T cells produce less IL-13, IL-5, and IL-4 and more tumor-necrosis factor, a known direct target of miR-19 [73,74]. Mechanistically, miR-19 was shown to promote Th2 cytokine production and amplify inflammatory signaling by direct targeting of the inositol phosphatase PTEN, the signaling inhibitor SOCS1 and the deubiquitinase A20 [73].…”

“…For example, human airway-infiltrating T cells from asthma patients have been shown to overexpress miR-19a, which promotes Th2 cytokine production, while conversely, its absence impairs Th2-cell responses [73]. Another example of an increase in the levels of a specific miRNA in association with inflammation is miR-155, which was found to be upregulated in inflammatory bowel disease (IBD), and miR-155 −/− mice displayed lower clinical scores and reduced systemic and mucosal Th1 and Th17 cytokines in an experimental colitis model [97].…”