Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity

Tur, Juan; Pereira-Lopes, Selma; Vico, Tania; Marín, Eros; Muñoz, Juan Pablo; Hernández‐Álvarez, María Isabel; Cardona, Père-Joan; Zorzano, António; Lloberas, Jorge; Celada, Antonio

doi:10.1016/j.celrep.2020.108079

Cited by 119 publications

(93 citation statements)

References 81 publications

(87 reference statements)

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“…Although the previous study showed that MFN2 deficiency results in a decreased phagocytosis in macrophages 12 , we did not observe any difference of Mtb phagocytosis between Mfn2 WT and Mfn2 CKO macrophages. The discrepancy might be due to different receptor–ligand interactions in macrophages between previous studies 12 and ours. Our data are also partly consistent with previous findings that MFN2 was required for IL-1β secretion during infection with RNA viruses 11 .…”

Section: Discussioncontrasting

confidence: 99%

“…We found that myeloid cell-specific MFN2 is essential for antimicrobial and inflammatory responses in vitro and in vivo during intracellular bacterial infection. These data partly correlate with a recent study reporting the protective role for myeloid MFN2 in innate immune responses during sepsis and bacterial infection 12 . Although the previous study showed that MFN2 deficiency results in a decreased phagocytosis in macrophages 12 , we did not observe any difference of Mtb phagocytosis between Mfn2 WT and Mfn2 CKO macrophages.…”

Section: Discussionsupporting

confidence: 91%

“…These data partly correlate with a recent study reporting the protective role for myeloid MFN2 in innate immune responses during sepsis and bacterial infection 12 . Although the previous study showed that MFN2 deficiency results in a decreased phagocytosis in macrophages 12 , we did not observe any difference of Mtb phagocytosis between Mfn2 WT and Mfn2 CKO macrophages. The discrepancy might be due to different receptor–ligand interactions in macrophages between previous studies 12 and ours.…”

Section: Discussionsupporting

confidence: 91%

“…Therefore, our work suggests that MFN2 functions in the suppression of macrophage differentiation into the M2 phenotype as well as driving aerobic glycolysis and inflammatory responses through HIF-1α during infection. The role of MFN2 in maintaining aerobic glycolysis seems to be unique in the settings of infection and inflammation, because there was no significant difference in glycolysis between unstimulated/uninfected Mfn2 WT and Mfn2 CKO macrophages 12 . In addition, MFN1/2 depletion was shown to promote the glycolytic metabolic reprogramming in mouse embryonic fibroblasts 19 , suggesting that MFN2 controls intracellular metabolism in a context-dependent manner.…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, the association between MFN2 and NLRP3 is required for inflammasome activation in response to RNA viruses 11 . Recently, MFN2 functions in macrophages have been reported in terms of inflammatory responses during bacterial infection and sepsis 12 ; however, the mechanisms by which MFN2 regulates innate host defense against intracellular bacterial infection remain to be characterized. In addition, whether MFN2 is involved in the regulation of immunometabolism and xenophagy, both of which are critically related to innate defense 13 , remains largely overlooked.…”

Section: Introductionmentioning

confidence: 99%

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Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice

et al. 2021

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Mitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintenance of aerobic glycolysis and xenophagy via hypoxia-inducible factor (HIF)-1α during intracellular bacterial infection. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection. Mechanistically, MFN2 was required for the enhancement of inflammatory signaling through optimal induction of aerobic glycolysis via HIF-1α, which is activated by mitochondrial respiratory chain complex I and reactive oxygen species, in macrophages. MFN2 did not impact mitophagy during infection; however, it promoted xenophagy activation through HIF-1α. In addition, MFN2 interacted with the late endosomal protein Rab7, to facilitate xenophagy during mycobacterial infection. Our findings reveal the mechanistic regulations by which MFN2 tailors the innate host defense through coordinated control of immunometabolism and xenophagy via HIF-1α during bacterial infection.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice

et al. 2021

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A multifunctional nanoaggregate‐based system for detection of rheumatoid arthritis via Optoacoustic/NIR‐II fluorescent imaging and therapy via inhibiting JAK‐STAT/NF‐κB/NLRP3 pathways

Chen,

She

et al. 2023

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Rheumatoid arthritis (RA) is a debilitating autoimmune disease that causes chronic pain and serious complications, presenting a significant challenge to treat. Promising approaches for treating RA involve signaling pathways modulation and targeted therapy. To this end, a multifunctional nanosystem, TPC‐U@HAT, has been designed for RA therapy, featuring multitargeting, dual‐stimuli response, and on‐demand drug release capabilities. TPC‐U@HAT is composed of a probe/prodrug TPC, a JAK1 kinase inhibitor upadacitinib, and the drug carrier HAT. TPC is composed of an aggregation‐induced emission (AIE)‐active NIR‐II chromophore TPY and an NF‐κB/NLRP3 inhibitor caffeic acid phenethyl ester (CAPE), connected via boronic ester bond which serves as the reactive‐oxygen‐species‐responsive linker. The carrier, HAT, is created by grafting bone‐targeting alendronate and hydrophobic tocopheryl succinate onto hyaluronic acid chains, which can encapsulate TPC and upadacitinib to form TPC‐U@HAT. Upon intravenous injection into mice, TPC‐U@HAT accumulates at inflamed lesions of RA through both active and passive targeting, and the overexpressed hyaluronidase and H2O2 therein cleave the hyaluronic acid polymer chains and boronate bonds, respectively. This generates an AIE‐active chromophore for detection and therapeutic evaluation of RA via both optoacoustic imaging and NIR‐II fluorescent imaging and concomitantly releases CAPE and upadacitinib to exert efficacious therapy by inhibiting NF‐κB/NLRP3 and JAK‐STAT pathways.

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Polysaccharide‐Based Stimulus‐Responsive Nanomedicines for Combination Cancer Immunotherapy

Liu

Yan

et al. 2023

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According to the World Health Organization, there were approximately 9.96 million deaths from cancer in 2020. Although researchers are actively searching for new treatments, the outcomes have been unsatisfactory, with limited improvement in the five-year survival rates. [2] Until now, immunotherapy has become one of the four pillars of clinical cancer treatment, along with surgery, chemotherapy, and radiotherapy. [3] It endows the body with the ability to eliminate tumors and prevent recurrence by stimulating the immune system, thus extending the survival time of patients. [4] Checkpoint inhibitors, pericyte therapy, lymphocyte-promoting cytokines, agonistic antibodies against co-stimulatory receptors, and cancer vaccines have been developed in recent years. [5] Due to the limited targeting and inherent toxicity of immune medicines, systemic use may result in autoimmune illness or non-specific inflammation. [6,7] In addition, tumor heterogeneity, clonal diversity, complex genetic mutations, and complex microenvironment all contribute to the poor outcomes of current tumor treatments. [8,9] Fortunately, previous studies have demonstrated that chemotherapy, photodynamic therapy (PDT), and photothermal therapy (PTT) can induce immunogenic cell death (ICD), which can enhance the immunotherapy effect. [10,11] However, the precise delivery of the co-therapeutic agents to the tumor site becomes the main challenge. [12] The rapid development of nanotechnology has promoted the application of nanomedicines in tumor therapy. [13] Nanomedicines can accumulate at tumor sites via the enhanced permeability and retention (EPR) effect and deliver drugs to specific tumor cells, thereby reducing off-target toxicity. [14,15] Notably, stimulus-responsive nanomedicines as a promising drug delivery method have received more and more attention. [16,17] The smart nano-platforms can achieve rapid drug release in response to external stimulus (ultrasound, mechanical stimuli, magnetic fields, lasers, etc.) or internal stimulus in the tumor microenvironment (TME) (weak acidity, high glutathione (GSH) levels, reactive oxygen species (ROS), enzymes, adenosine triphosphate (ATP), etc.), thus improving tumor treatment outcomes. [18] Polysaccharides, a family of potential biomaterials, possess unique advantages such as unique physicochemical properties, Cancer immunotherapy is a promising antitumor approach, whereas nontherapeutic side effects, tumor microenvironment (TME) intricacy, and low tumor immunogenicity limit its therapeutic efficacy. In recent years, combination immunotherapy with other therapies has been proven to considerably increase antitumor efficacy. However, achieving codelivery of the drugs to the tumor site remains a major challenge. Stimulus-responsive nanodelivery systems show controlled drug delivery and precise drug release. Polysaccharides, a family of potential biomaterials, are widely used in the development of stimulus-responsive nanomedicines due to their unique physicochemical properties, biocompatibility, and modifiab...

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Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity

Abstract: Highlights d In macrophages, LPS-induced ROS production requires mitochondrial mitofusin 2 d Mfn2 is required for the production of cytokines, phagocytosis, and antigen processing d Survival from bacterial infection or septic shock is compromised in Mfn2 À/À mice

Cited by 119 publications

References 81 publications

Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice

Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice

A multifunctional nanoaggregate‐based system for detection of rheumatoid arthritis via Optoacoustic/NIR‐II fluorescent imaging and therapy via inhibiting JAK‐STAT/NF‐κB/NLRP3 pathways

Polysaccharide‐Based Stimulus‐Responsive Nanomedicines for Combination Cancer Immunotherapy

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