Novel Function of Cyclooxygenase-2: Suppressing Mycobacteria by Promoting Autophagy via the Protein Kinase B/Mammalian Target of Rapamycin Pathway

Xiong, Wenjing; Wen, Qian; Du, Xialin; Wang, Jinli; He, Wenting; Wang, Ruining; Hu, Shengfeng; Zhou, Xinying; Yang, Jiahui; Gao, Yuchi; Ma, Li

doi:10.1093/infdis/jiy033

Cited by 21 publications

(28 citation statements)

References 45 publications

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“…These observations demonstrated that COX-2 participates in the regulation of autophagy induced by WNT5A following M. tuberculosis infection. It has recently been reported that activation of autophagy by COX-2 in macrophages is through AKT/mTOR signaling to suppress mycobacterial survival in bone marrow-derived macrophages (36). Consistently, a decrease in activation of AKT and mTOR was observed in MDMs exposed to rhWNT5A, whereas small interfering WNT5A (si-WNT5A) upregulated their levels (Fig.…”

Section: Il-36g Mediated the Bactericidal Activity Partly Through Thesupporting

confidence: 72%

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

Gao

Wen

et al. 2019

The Journal of Immunology

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Mycobacterium tuberculosis, which primarily infects mononuclear phagocytes, remains the leading bacterial cause of enormous morbidity and mortality because of bacterial infections in humans throughout the world. The IL-1 family of cytokines is critical for host resistance to M. tuberculosis. As a newly discovered subgroup of the IL-1 family, although IL-36 cytokines have been proven to play roles in protection against M. tuberculosis infection, the antibacterial mechanisms are poorly understood. In this study, we demonstrated that IL-36γ conferred to human monocyte-derived macrophages bacterial resistance through activation of autophagy as well as induction of WNT5A, a reported downstream effector of IL-1 involved in several inflammatory diseases. Further studies showed that WNT5A could enhance autophagy of monocyte-derived macrophages by inducing cyclooxygenase-2 (COX-2) expression and in turn decrease phosphorylation of AKT/mTOR via noncanonical WNT signaling. Consistently, the underlying molecular mechanisms of IL-36γ function are also mediated by the COX-2/AKT/mTOR signaling axis. Altogether, our findings reveal a novel activity for IL-36γ as an inducer of autophagy, which represents a critical inflammatory cytokine that control the outcome of M. tuberculosis infection in human macrophages.

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Section: Il-36g Mediated the Bactericidal Activity Partly Through Thesupporting

confidence: 72%

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

Gao

Wen

et al. 2019

The Journal of Immunology

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“…In this regard, it has been shown that cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through the activation of PGE2production 11 and that nicotine induces cell stress and autophagy mediated by COX-2 activation and PGE2 production in human colon cancer cells 12 . Furthermore, it was recently described that the expression of COX-2 contributes to increase autophagy and therefore to eliminate Mtb in bone marrow murine derived macrophages 13 . Nevertheless, this modulation has not been described yet in primary human cells.…”

Section: Resultsmentioning

confidence: 99%

“…Besides, kidney autophagy levels were shown to decrease after silencing PGES-2 33 . Importantly, Xiong et al reported that COX-2 suppresses mycobacterial growth in murine macrophages by promoting autophagy via the AKT/mTOR pathway 13 . Strikingly, other authors described that the PGE2 reverses vitamin D3-induced autophagy in macrophages infected with Mtb 34 .…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive role of PGE2 during human tuberculosis

Pellegrini

Tateosian

Morelli

et al. 2020

Preprint

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Prostaglandin E2 (PGE2), an active lipid compound derived from arachidonic acid, regulates different stages of the immune response of the host during several pathologies such as chronic infections or cancer. Manipulation of PGE2 levels was proposed as an approach for countering the Type I IFN signature of tuberculosis (TB), but very limited information exists about this pathway in patients with active TB. Here, we demonstrated that PGE2 exerts a potent immunosuppressive action during the immune response of the human host against M. tuberculosis. Thus, we showed that PGE2 inhibited both lymphoproliferation and cytokine production of proinflammatory cytokines, together with a significant reduction of the surface expression of several immunological receptors in human cells. However, PGE2 promoted the autophagic flux of antigen-stimulated monocytes, even in the presence of IFNα. In this way, the attenuation of inflammation and immunopathology caused by an excessive immune response emerges as an attractive therapeutic target. Together, our findings contribute to the knowledge of Mtb-resistance mediated by PGE2 and highlight the potential of this lipid mediator as a tool to improve anti-TB treatment.

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“…Autophagy is an efficient cellular process for the host to eliminate pathogens, and COX-2 was reported to be beneficial for the clearance of M. tuberculosis by promoting autophagy (Xiong et al, 2018). To explore the effect of COX-2 inhibition on autophagy in ExPEC-infected macrophages, the expression level of the autophagy formation marker LC3, which is converted into LC3-II from LC3-I, was assessed in the study.…”

Section: Cox-2 Inhibition Attenuated Macrophage Autophagy During Expementioning

confidence: 99%

“…COX-2 mediated PG production was also demonstrated to be involved in inducing autophagy in various physiological processes (Kar et al, 2009;Choi et al, 2014;Pelissier-Rota et al, 2015). However, the function of autophagy in ExPEC infection may vary depending on the strain and pathotype, and the association between ExPEC-induced COX-2 expression and autophagy formation has not yet been elucidated (Xiong et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-2 Inhibition Reduces Autophagy of Macrophages Enhancing Extraintestinal Pathogenic Escherichia coli Infection

Chen

Jiang

2020

Front. Microbiol.

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Extraintestinal pathogenic Escherichia coli (ExPEC) is one of the top pathogens responsible for bloodstream infection and severe, often fatal, sepsis. Although the virulence factors and host immune responses to ExPEC infection have been investigated, the responses to a particular ExPEC strain could be very different. In this study, we investigated the mechanisms of Cyclooxygenase-2 (COX-2) upregulation in influencing the host defenses against infection of ExPEC XM O2:K1:H7. Our results demonstrated that ExPEC XM O2:K1:H7 infection in mouse and RAW264.7 macrophages leads to COX-2 up-regulation, and COX-2 inhibition significantly enhances ExPEC infection. The up-regulation of COX-2 in macrophages was mediated by Tolllike receptor 4 (TLR4) through the activation of p38 and extracellular signal-regulated kinase/Mitogen-activated protein kinase (ERK/MAPK) pathways. Further studies showed that COX-2 inhibition significantly decreased autophagy in macrophages during ExPEC XM O2:K1:H7 infection. Autophagy inhibition significantly enhanced, while induction reduced ExPEC XM O2:K1:H7 survival in macrophages. In addition, COX-2 inhibition significantly increased macrophage cell death during ExPEC XM O2:K1:H7 infection and increased the expression of anti-inflammatory cytokine interleukin-10 (IL-10). Our results indicate that COX-2 up-regulation benefits host defense against ExPEC XM O2:K1:H7 infection by increasing autophagy in macrophages and by reducing IL-10 expression and macrophage cell death during ExPEC infection.

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Novel Function of Cyclooxygenase-2: Suppressing Mycobacteria by Promoting Autophagy via the Protein Kinase B/Mammalian Target of Rapamycin Pathway

Cited by 21 publications

References 45 publications

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

Immunosuppressive role of PGE2 during human tuberculosis

Cyclooxygenase-2 Inhibition Reduces Autophagy of Macrophages Enhancing Extraintestinal Pathogenic Escherichia coli Infection

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