MicroRNA let-7 Modulates the Immune Response to Mycobacterium tuberculosis Infection via Control of A20, an Inhibitor of the NF-κB Pathway

Kumar, Manish; Sahu, Sanjaya Kumar; Kumar, Ranjeet; Subuddhi, Arijita; Maji, Ranjan Kumar; Jana, Kuladip; Gupta, Pushpa; Raffetseder, Johanna; Lerm, Maria; Ghosh, Zhumur; Loo, Geert; Beyaert, Rudi; Gupta, Umesh Datta; Kundu, Manikuntala; Basu, Joyoti

doi:10.1016/j.chom.2015.01.007

Cited by 224 publications

(204 citation statements)

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“…Furthermore, emerging evidence indicates that certain single let-7 family members play individual roles in different types of immune cells. For example, let-7f modulates macrophage immune response to infection by Mycobacterium tuberculosis through repressing A20 (Kumar et al, 2015), whereas let-7a plays a pro-inflammatory role in an experimental asthma model by targeting IL-13 (Kumar et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

et al. 2018

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Section: Discussionmentioning

confidence: 99%

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

et al. 2018

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“…A20 inhibits inflammation through interfering with NF-B, MAPK, and interferon regulatory factor pathways and regulates cellular functions, including apoptosis, necroptosis, and autophagy, in several models of inflammatory diseases and cell types (28). Furthermore, increased A20 expression or activity has also been associated with dampening numerous disease outcomes (29,30). Thus, there is great interest in manipulating A20 for therapeutic benefit (31).…”

Section: Tlr9 and A20 In Periodontal Inflammationmentioning

confidence: 99%

“…It is possible that, although it is still a functional protein in the course of periodontitis, A20 expression does not reach sufficient levels to facilitate the resolution of inflammation. Thus, the questions that remain to be answered are how A20 levels and activity are regulated and whether the manipulation of A20 can prevent further periodontal tissue destruction, similar to its effects in other inflammatory diseases (29)(30)(31).…”

Section: Tlr9 and A20 In Periodontal Inflammationmentioning

confidence: 99%

Interplay of Toll-Like Receptor 9, Myeloid Cells, and Deubiquitinase A20 in Periodontal Inflammation

et al. 2017

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Toll-like receptor 9 (TLR9)-deficient (TLR9 Ϫ/Ϫ ) mice are resistant to periodontitis, a disease characterized by a dysbiotic microbiota and deregulated immune response and resulting in tooth loss and various systemic conditions. However, the mechanisms and biological pathways by which TLR9 instigates periodontal inflammation are yet to be identified. In a ligature-induced model of periodontitis, we demonstrate that TLR9 Ϫ/Ϫ mice exhibited significantly less alveolar bone loss than their wild-type (WT) counterparts. Consistent with the disease phenotype, gingival tissues showed significantly more inflammatory cell infiltration in the WT ligated but not in the TLR9 Ϫ/Ϫ ligated mice compared to the unligated controls. The peritoneal infection model using Porphyromonas gingivalis, a keystone pathogen for periodontitis, revealed reduced neutrophils in TLR9 Ϫ/Ϫ mice on day 1 postinfection compared to the levels in WT mice. Transcriptomics analyses showed increased expression of A20 (tumor necrosis factor alpha [TNF-␣]-induced protein 3 [TNFAIP3]), an inhibitor of the NF-B pathway and a negative regulator of TLR signaling, in ligated TLR9 Ϫ/Ϫ mouse gingival tissues compared to its expression in the WT. Ex vivo, TLR9 Ϫ/Ϫ bone marrow-derived macrophages produced more A20 than WT cells following P. gingivalis challenge. Clinically, A20 was modestly upregulated in human gingival tissue specimens from chronic periodontitis patients, further confirming the biological relevance of A20 in periodontal inflammation. We conclude that TLR9 modulates periodontal disease progression at both the cellular and molecular level and identify A20 as a novel downstream signaling molecule in the course of periodontal inflammation. Understanding the regulation of the TLR9 signaling pathway and the involvement of A20 as a limiting factor of inflammation will uncover alternative therapeutic targets to treat periodontitis and other chronic inflammatory diseases.

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“…It remains speculative whether let-7 modulates IL-10 production in this setting, and if the generation of an immunosuppressive milieu confers a survival benefit for HIV-1 [71]. Another study has shown that in macrophages infected with Mycobacterium tuberculosis, let-7 is downregulated, which in turn promotes bacterial survival and suppresses responses [72]. 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.…”

Section: Mirna Regulation Of Il-2mentioning

confidence: 99%

Cross‐regulation between cytokine and microRNA pathways in T cells

et al. 2015

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microRNA (miRNA) mediated regulation of protein expression has emerged as an important mechanism in T-cell physiology, from development and survival to activation, proliferation, and differentiation. One of the major classes of proteins involved in these processes are cytokines, which are both key input signals and major products of T-cell function. Here, we summarize the current data on the molecular cross-talk between cytokines and miRNAs: how cytokines regulate miRNA expression, and how specific miRNAs control cytokine production in T cells. We also describe the inflammatory consequences of deregulating the miRNA/cytokine axis in mice and humans. We believe this topical area will have key implications for immune modulation and treatment of autoimmune pathology. Keywords:Cytokines r Inflammation r miRNA r T cells microRNAs as regulators of protein expressionBiological processes require the integration of environmental stimuli at the level of gene expression. The robustness of genetic networks depends on the distinction between physiological responses (to particular cues) and biological "noise" (stochastic variations), which can be achieved, for example, by establishing feed-forward transcriptional loops. Over the past two decades, a new mechanism that interacts with transcriptional loops and sets additional thresholds, which enable cells to filter physiological signals from noise has emerged; this mechanism regulates gene expression at the posttranscriptional level and relies on microRNAs (miRNAs; reviewed in [1]). These are an abundant class of evolutionarily conserved small noncoding (untranslated) RNA species that control target mRNA stability, degradation, and translation, thus affecting the majority of mammalian genes [2].Correspondence: Dr. Anita Q. Gomes e-mail: anitagomes@medicina.ulisboa.ptIn the conventional miRNA biogenesis pathway, RNA polymerase II transcribed pri-miRNAs are processed by the nuclear RNase III enzyme Drosha (complexed with DGCR8) to generate 60-70 nt stem-loop intermediates, the pre-miRNAs, that are further processed into 19-24mers in the cytoplasm by another key RNase III, Dicer. Mature miRNAs are then incorporated into RNAinduced silencing complexes, whose core components are proteins of the Argonaute family (Ago1-4), which use the 5 end (nucleotides 2-8) "seed sequence" of the miRNA to recognize complementary mRNA transcripts (mostly in their 3 untranslated region) for deadenylation or inhibition of translation, ultimately resulting in mRNA decapping and decay (reviewed in [3,4]).Unique spatial and temporal expression patterns in distinct hematopoietic cell lineages are suggestive of multiple roles for miRNAs in hematopoiesis, self-tolerance, and in immune responses, which have been explored over the past decade (reviewed in [5,6]). Over a 100 different miRNAs have been shown to be expressed by cells of the immune system, where * These authors contributed equally to this work as first authors. * * These authors contributed equally to this work as last authors.C 2015 WILEY-VCH Ve...

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MicroRNA let-7 Modulates the Immune Response to Mycobacterium tuberculosis Infection via Control of A20, an Inhibitor of the NF-κB Pathway

Cited by 224 publications

References 50 publications

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

Interplay of Toll-Like Receptor 9, Myeloid Cells, and Deubiquitinase A20 in Periodontal Inflammation

Cross‐regulation between cytokine and microRNA pathways in T cells

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