Mycobacterium tuberculosis Controls MicroRNA-99b (miR-99b) Expression in Infected Murine Dendritic Cells to Modulate Host Immunity

Singh, Yogesh; Kaul, Vandana; Mehra, Alka; Chatterjee, Samit; Tousif, Sultan; Dwivedi, Ved Prakash; Suar, Mrutyunjay; Kaer, Luc Van; Bishai, William R.; Das, Gobardhan

doi:10.1074/jbc.c112.439778

Cited by 151 publications

(118 citation statements)

References 25 publications

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“…Interestingly, all 19 miRNAs showed significantly elevated expression in the THC/SIV group compared to the VEH/SIV group (Table 4; see also Table S8 in the supplemental material). Among the these, miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187 have been previously reported to regulate inflammation (48)(49)(50)(51)(52)(53)(54). As shown in Fig.…”

Section: Plasma and Intestinal Viral Loads Cd4 And Cd8 T Cell Statusmentioning

confidence: 99%

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chandra

Kumar

Torben

et al. 2015

J Virol

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Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of ⌬9 -tetrahydrocannabinol (⌬ 9 -THC) inhibited viral replication and intestinal inflammation and slowed disease progression. Persistent gastrointestinal disease/inflammation has been proposed to facilitate microbial translocation and systemic immune activation and promote disease progression. Cannabinoids including ⌬ 9 -THC attenuated intestinal inflammation in mouse colitis models and SIV-infected rhesus macaques. To determine if the anti-inflammatory effects of ⌬ 9 -THC involved differential microRNA (miRNA) modulation, we profiled miRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the intestine of uninfected macaques receiving ⌬ 9 -THC (n ‫؍‬ 3) and SIV-infected macaques administered either vehicle (VEH/ SIV; n ‫؍‬ 4) or THC (THC/SIV; n ‫؍‬ 4). Chronic ⌬ 9 -THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days p.i. At 60 days p.i., ϳ28% of miRNAs showed decreased expression in the VEH/SIV group compared to none showing decrease in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187, previously been shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator, was confirmed as a direct miR-99b target. A significant increase in NOX4 ؉ crypt epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. These results support a role for differential miRNA induction in THC-mediated suppression of intestinal inflammation. Whether similar miRNA modulation occurs in other tissues requires further investigation. IMPORTANCE Gastrointestinal (GI) tract disease/inflammation is a hallmark of HIV/SIV infection. Previously, we showed that chronic treatment of SIV-infected macaques with ⌬9 -tetrahydrocannabinol (⌬ 9 -THC) increased survival and decreased viral replication and infection-induced gastrointestinal inflammation. Here, we show that chronic THC administration to SIV-infected macaques induced an anti-inflammatory microRNA expression profile in the intestine at 60 days p.i. These included several miRNAs bioinformatically predicted to directly target CXCL12, a chemokine known to regulate lymphocyte and macrophage trafficking into the intestine. Specifically, miR-99b was significantly upregulated in THC-treated SIV-infected macaques and confirmed to directly target NADPH oxidase 4 (NOX4), a reactive oxygen species generator known to damage intestinal epithelial cells. Elevated miR-99b expression was associated with a significantly decreased number of NOX4...

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Section: Plasma and Intestinal Viral Loads Cd4 And Cd8 T Cell Statusmentioning

confidence: 99%

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chandra

Kumar

Torben

et al. 2015

J Virol

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“…Several studies suggest that key TBprotective cytokines, including TNF-α and IFN-γ, are regulated by miR-125b and miR-29, respectively (16,17). Moreover, screening approaches have tentatively pointed to miRNA signatures characteristic of active TB (18)(19)(20)(21)(22). Yet, no functional role in TB for any of these miRNAs has been elucidated, including the effects on chemokines and cell migration.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment

et al. 2013

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The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223 -/-mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223 -/-animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.

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“…Recent study showed that miR-155 is highly upregulated in RAW264.7 cells and BMDMs in response to M. tuberculosis infection and ESAT-6 stimulation, and it plays a role in the downregulation of BTB and CNC homology 1 and SHIP1 to modulate host innate immune responses (44). Additionally, another study reported that miR-99b is highly upregulated in M. tuberculosis H37Rv-infected dendritic cells and macrophages, and it contributes to the enhancement of intracellular bacterial growth and downregulation of proinflammatory cytokines (45). Together with the present data, these studies suggest that the expression of multiple miRNAs is increased by M. tuberculosis infection, which may contribute to host evasion mechanisms.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-125a Inhibits Autophagy Activation and Antimicrobial Responses during Mycobacterial Infection

Kim

Yuk

Kim

et al. 2015

The Journal of Immunology

120

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MicroRNAs (miRNAs) are small noncoding nucleotides that play critical roles in the regulation of diverse biological functions, including the response of host immune cells. Autophagy plays a key role in activating the antimicrobial host defense against Mycobacterium tuberculosis. Although the pathways associated with autophagy must be tightly regulated at a posttranscriptional level, the contribution of miRNAs and whether they specifically influence the activation of macrophage autophagy during M. tuberculosis infection are largely unknown. In this study, we demonstrate that M. tuberculosis infection of macrophages leads to increased expression of miRNA-125a-3p (miR-125a), which targets UV radiation resistance-associated gene (UVRAG), to inhibit autophagy activation and antimicrobial responses to M. tuberculosis. Forced expression of miR-125a significantly blocked M. tuberculosis–induced activation of autophagy and phagosomal maturation in macrophages, and inhibitors of miR-125a counteracted these effects. Both TLR2 and MyD88 were required for biogenesis of miR-125a during M. tuberculosis infection. Notably, activation of the AMP-activated protein kinase significantly inhibited the expression of miR-125a in M. tuberculosis–infected macrophages. Moreover, either overexpression of miR-125a or silencing of UVRAG significantly attenuated the antimicrobial effects of macrophages against M. tuberculosis. Taken together, these data indicate that miR-125a regulates the innate host defense by inhibiting the activation of autophagy and antimicrobial effects against M. tuberculosis through targeting UVRAG.

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Mycobacterium tuberculosis Controls MicroRNA-99b (miR-99b) Expression in Infected Murine Dendritic Cells to Modulate Host Immunity

Cited by 151 publications

References 25 publications

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment

MicroRNA-125a Inhibits Autophagy Activation and Antimicrobial Responses during Mycobacterial Infection

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Mycobacterium tuberculosis Controls MicroRNA-99b (miR-99b) Expression in Infected Murine Dendritic Cells to Modulate Host Immunity

Cited by 151 publications

References 25 publications

Chronic Administration of Δ 9 -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chronic Administration of Δ 9 -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment

MicroRNA-125a Inhibits Autophagy Activation and Antimicrobial Responses during Mycobacterial Infection

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Product

Resources

About

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques