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Inflammatory response is modulated by lincRNACox2 via the NF??B pathway in macrophages infected by Mycobacterium tuberculosis.

ABSTRACT: Long intergenic non-coding RNAs (lincRNAs) are long non?coding transcripts from the intergenic regions of annotated protein?coding genes. lincRNA cyclooxygenase 2 (Cox2) is an early?primary response gene regulated by the NF??B signaling pathway in macrophages. It was found that lincRNACox2 was significantly increased in patients with the Mycobacterium tuberculosis (M. tuberculosis) H37Ra strain infection and macrophages, using reverse transcription-quantitative PCR (RT?qPCR). ELISA, western blotting and RT?qPCR results indicated that the inflammatory response factors tumor necrosis factor??, interferon??, interleukin?6, Cox2 and inducible nitric oxide synthase were significantly increased in H37Ra infected macrophages. In addition, the inflammatory regulating proteins NF??B and Stat3 were significantly increased in H37Ra infected macrophages but decreased in lincRNACox2 knockdown macrophages infected with H37Ra. Moreover, the knockdown of lincRNACox2 increased the apoptotic rate of H37Ra infected macrophages and facilitated the proliferation of H37Ra. Collectively, the present results suggested that lincRNACox2 may be required for the activation of NF??B and Stat3, in order to regulate inflammatory responses involved in resistance to M. tuberculosis infection.

SUBMITTER: Li D

PROVIDER: S-EPMC7185307 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Inflammatory response is modulated by lincRNACox2 via the NF‑κB pathway in macrophages infected by Mycobacterium tuberculosis.

Li Danye D Gao Caiyan C Zhao Ling L Zhang Yongming Y

Molecular medicine reports 20200402 6

Long intergenic non-coding RNAs (lincRNAs) are long non‑coding transcripts from the intergenic regions of annotated protein‑coding genes. lincRNA cyclooxygenase 2 (Cox2) is an early‑primary response gene regulated by the NF‑κB signaling pathway in macrophages. It was found that lincRNACox2 was significantly increased in patients with the Mycobacterium tuberculosis (M. tuberculosis) H37Ra strain infection and macrophages, using reverse transcription-quantitative PCR (RT‑qPCR). ELISA, western blot ...[more]

PMID: 32323851

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Project description:BackgroundTuberculosis (TB), a bacterial infection caused by Mycobacterium tuberculosis (Mtb) remains a significant health problem worldwide with a third of the world population infected and nearly nine million new cases claiming 1.1 million deaths every year. The outcome following infection by Mtb is determined by a complex and dynamic host-pathogen interaction in which the phenotype of the pathogen and the immune status of the host play a role. However, the molecular mechanism by which Mtb strains induce different responses during intracellular infection of the host macrophage is not fully understood. To explore the early molecular events triggered upon Mtb infection of macrophages, we studied the transcriptional responses of murine bone marrow-derived macrophages (BMM) to infection with two clinical Mtb strains, CDC1551 and HN878. These strains have previously been shown to differ in their virulence/immunogenicity in the mouse and rabbit models of pulmonary TB.ResultsIn spite of similar intracellular growth rates, we observed that compared to HN878, infection by CDC1551 of BMM was associated with an increased global transcriptome, up-regulation of a specific early (6 hours) immune response network and significantly elevated nitric oxide production. In contrast, at 24 hours post-infection of BMM by HN878, more host genes involved in lipid metabolism, including cholesterol metabolism and prostaglandin synthesis were up-regulated, compared to infection with CDC1551.In association with the differences in the macrophage responses to infection with the 2 Mtb strains, intracellular CDC1551 expressed higher levels of stress response genes than did HN878.ConclusionsIn association with the early and more robust macrophage activation, intracellular CDC1551 cells were exposed to a higher level of stress leading to increased up-regulation of the bacterial stress response genes. In contrast, sub-optimal activation of macrophages and induction of a dysregulated host cell lipid metabolism favored a less stressful intracellular environment for HN878. Our findings suggest that the ability of CDC1551 and HN878 to differentially activate macrophages during infection probably determines their ability to either resist host cell immunity and progress to active disease or to succumb to the host protective responses and be driven into a non-replicating latent state in rabbit lungs.

Project description:Mycobacterium tuberculosis (Mtb) remains a great threat to global health, killing more people than any other single infectious agent and causing uncontrollable inflammation in the host. Poorly controlled inflammatory processes can be deleterious and result in immune exhaustion. The current tuberculosis (TB) control is facing the challenge of drugs deficiency, especially in the context of increasingly multidrug resistant (MDR) TB. Under this circumstance, alternative host-directed therapy (HDT) emerges timely which can be exploited to improve the efficacy of TB treatment and disease prognosis by targeting the host. Here, we established the in vitro infection model of Mtb macrophages with H37Ra strain to seek effective anti-TB active agent. The present study showed that Guttiferone K, isolated from Garcinia yunnanensis, could significantly inhibit Mtb-induced inflammation in RAW264.7 and primary peritoneal macrophages. It was evidenced by the decreased production of inflammatory mediators, including interleukin-1? (IL-1?), tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Further studies with immunoblotting and immunofluorescence revealed that Guttiferone K obviously inhibits the nuclear factor-kappa B (NF-?B) both in RAW264.7 and primary peritoneal macrophages relying on the TLR/IRAK-1 pathway. Guttiferone K could also suppress the NLRP3 inflammasome activity and induce autophagy by inhibiting the protein kinase B (p-Akt) and mammalian target of rapamycin (mTOR) phosphorylation at Ser473 and Ser2448 in both cell lines. Thus, Guttiferone K possesses significant anti-inflammatory effect, alleviating Mtb-induced inflammation with an underlying mechanism that targeting on the TLR/IRAK-1 pathway and inhibiting the downstream NF-?B and Akt/mTOR signaling pathways. Together, Guttiferone K can be an anti-inflammatory agent candidate for the design of new adjunct HDT drugs fighting against tuberculosis.

Project description:A high intracellular bacillary load of Mycobacterium tuberculosis in macrophages induces an atypical lysosomal cell death with early features of apoptosis that progress to necrosis within hours. Unlike classical apoptosis, this cell death mode does not appear to diminish M. tuberculosis viability. We previously reported that culturing heavily infected macrophages with naïve macrophages produced an antimicrobial effect, but only if naïve macrophages were added during the pre-necrotic phase of M. tuberculosis-induced cell death. In the present study we investigated the mechanism of antimicrobial activity in co-cultures, anticipating that efferocytosis of bacilli in apoptotic bodies would be required. Confocal microscopy revealed frustrated phagocytosis of M. tuberculosis-infected macrophages with no evidence that significant numbers of bacilli were transferred to the naïve macrophages. The antimicrobial effect of naïve macrophages was retained when they were separated from infected macrophages in transwells, and conditioned co-culture supernatants transferred antimicrobial activity to cultures of infected macrophages alone. Antimicrobial activity in macrophage co-cultures was abrogated when the naïve population was deficient in IL-1 receptor or when the infected population was deficient in inducible nitric oxide synthase. The participation of nitric oxide suggested a conventional antimicrobial mechanism requiring delivery of bacilli to a late endosomal compartment. Using macrophages expressing GFP-LC3 we observed the induction of autophagy specifically by a high intracellular load of M. tuberculosis. Bacilli were identified in LC3-positive compartments and LC3-positive compartments were confirmed to be acidified and LAMP1 positive. Thus, the antimicrobial effect of naïve macrophages acting on M. tuberculosis in heavily-infected macrophages is contact-independent. Interleukin-1 provides an afferent signal that induces an as yet unidentified small molecule which promotes nitric oxide-dependent antimicrobial activity against bacilli in autolysosomes of heavily infected macrophages. This cooperative, innate antimicrobial interaction may limit the maximal growth rate of M. tuberculosis prior to the expression of adaptive immunity in pulmonary tuberculosis.

Dataset Information

Inflammatory response is modulated by lincRNACox2 via the NF??B pathway in macrophages infected by Mycobacterium tuberculosis.

Publications

Inflammatory response is modulated by lincRNACox2 via the NF‑κB pathway in macrophages infected by Mycobacterium tuberculosis.

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