Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection

Zhu, Bibo; Wu, Yue; Huang, Su; Zhang, Ruixuan; Son, Young Min; Li, Chaofan; Cheon, In Su; Gao, Xiaohuan; Wang, Min; Chen, Yao; Zhou, Xian; Nguyen, Quynh; Phan, Anthony T.; Behl, Supriya; Taketo, Makoto Mark; Mack, Matthias; Shapiro, Virginia Smith; Zeng, Hu; Ebihara, Hideki; Mullon, John J.; Edell, Eric S.; Reisenauer, Janani; Demirel, Nadir; Kern, Ryan; Chakraborty, Rana; Cui, Weiguo; Kaplan, Mark H.; Zhou, Xiaobo; Goldrath, Ananda W.; Sun, Jie

doi:10.1016/j.immuni.2021.04.001

Cited by 86 publications

(114 citation statements)

References 76 publications

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“…Macrophages are important mediators of lung inflammation during COVID-19 disease [42]. As a result of hypoxia in the lung, elevated HIF-1α activity on immune innate cells contribute to severity [43,44]. In this scenario, promoting systemic HIF-1α activity through pharmacological intervention in severe COVID-19 patients might be detrimental.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Prieto-Fernández

Egia-Mendikute

Vila-Vecilla

et al. 2021

Emerging Microbes & Infections

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A main clinical parameter of COVID-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor binding domain (RBD) and the S1 subunit (S1) of the spike protein of SARS-CoV-2 to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2 and neuropilin-1 (NRP1), which might in part explain the observed reduction of the infection rate. In addition, hypoxia inhibits the binding of the spike to NCI-H460 human lung epithelial cells by decreasing the cell surface levels of heparan sulfate (HS), a known attachment receptor of SARS-CoV-2. This interaction is also reduced by lactoferrin, a glycoprotein that blocks HS moieties on the cell surface. The expression of syndecan-1, an HS-containing proteoglycan expressed in lung, is inhibited by hypoxia on a HIF-1α-dependent manner. Hypoxia or deletion of syndecan-1 results in reduced binding of the RBD to host cells. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signaling pathway might offer therapeutic opportunities for the treatment of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Prieto-Fernández

Egia-Mendikute

Vila-Vecilla

et al. 2021

Emerging Microbes & Infections

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“…Zhu et al studied the relationship between inflammatory and proliferative properties in alveolar macrophages [ 77 ]. In their study, a murine influenza viral pneumonia model was used, and authors found that β-catenin-mediated alveolar macrophage inflammatory activity increased host morbidity, while alveolar macrophage proliferation allowed the repopulation of reparative alveolar macrophages and tissue repair after viral clearance [ 77 ]. Activation of Wnt/β-catenin signaling reduced the proliferation of alveolar macrophages and promoted the generation of pro-inflammatory mediators by alveolar macrophages [ 77 ].…”

Section: Hif-dependent Regulation Of Lung Repair Following Inflammatory Lung Injurymentioning

confidence: 99%

Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair

Evans

2022

Cells

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Inflammatory lung injury is characterized by lung endothelial cell (LEC) death, alveolar epithelial cell (AEC) death, LEC–LEC junction weakening, and leukocyte infiltration, which together disrupt nutrient and oxygen transport. Subsequently, lung vascular repair is characterized by LEC and AEC regeneration and LEC–LEC junction re-annealing, which restores nutrient and oxygen delivery to the injured tissue. Pulmonary hypoxia is a characteristic feature of several inflammatory lung conditions, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19). The vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors (HIFs) 1 and 2. These transcription factors control the expression of a wide variety of target genes, which in turn mediate key pathophysiological processes including cell survival, differentiation, migration, and proliferation. HIF signaling in pulmonary cell types such as LECs and AECs, as well as infiltrating leukocytes, tightly regulates inflammatory lung injury and repair, in a manner that is dependent upon HIF isoform, cell type, and injury stimulus. The aim of this review is to describe the HIF-dependent regulation of inflammatory lung injury and vascular repair. The review will also discuss potential areas for future study and highlight putative targets for inflammatory lung conditions such as ALI/ARDS and severe COVID-19. In the development of HIF-targeted therapies to reduce inflammatory lung injury and/or enhance pulmonary vascular repair, it will be vital to consider HIF isoform- and cell-specificity, off-target side-effects, and the timing and delivery strategy of the therapeutic intervention.

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“…HIF-1α is a master regulator of aerobic glycolysis and plays a crucial role in macrophage polarization to the M1 phenotype associated with inflammation, and HIF-1α stabilization promotes IL-1α production ( Tannahill et al, 2013 ). Similarly, HIF-1α is upregulated in SARS-CoV-2 patients and promotes macrophage inflammatory responses ( Zhu et al, 2021a ). HIF-1α can also induce miR-210 to shift macrophages to a proinflammatory state while knocking down miR-210 limits the cytokine storm ( Virga et al, 2021 ).…”

Section: Glycolysis and Innate Immunitymentioning

confidence: 99%

“…Hypoxia-inducible factor-1 and c-Myc regulate glycolytic flux during viral infection. Under normoxic conditions, b-catenin specifically interacts with HIF-1α in alveolar macrophages (AMs) infected by respiratory viruses, thus regulating HIF-1α-driven glycolysis to promote excessive inflammation, leading to inhibition of AMs proliferation ( Zhu et al, 2021a ). Similarly, cellular mitochondrial oxidative phosphorylation is impaired by HCV infection, resulting in upregulation of HIF-1 and consequently glycolysis-related gene expression ( Ripoli et al, 2010 ).…”

Section: Glycolysis and Innate Immunitymentioning

confidence: 99%

“…Viruses can utilize glycolysis’s energy and molecular precursors for their infection and replication ( Passalacqua et al, 2019 ; Mansouri et al, 2020 ). In vitro and in vivo experiments during viral infections such as SARS-CoV-2 have found that increased aerobic glycolysis will cause inflammation and even lead to cytokine storms, resulting in increased viral replication ( Thai et al, 2014 ; Zhu et al, 2021a ). Recently, it has been shown that SARS-CoV-2 infection of human monocytes upregulates glycolytic genes, promoting virus replication and the expression of proinflammatory factors ( Codo et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis

Ren

Chen

et al. 2021

Front. Microbiol.

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Long noncoding RNA (LncRNA), a noncoding RNA over 200nt in length, can regulate glycolysis through metabolic pathways, glucose metabolizing enzymes, and epigenetic reprogramming. Upon viral infection, increased aerobic glycolysis providzes material and energy for viral replication. Mitochondrial antiviral signaling protein (MAVS) is the only protein-specified downstream of retinoic acid-inducible gene I (RIG-I) that bridges the gap between antiviral immunity and glycolysis. MAVS binding to RIG-I inhibits MAVS binding to Hexokinase (HK2), thereby impairing glycolysis, while excess lactate production inhibits MAVS and the downstream antiviral immune response, facilitating viral replication. LncRNAs can also regulate antiviral innate immunity by interacting with RIG-I and downstream signaling pathways and by regulating the expression of interferons and interferon-stimulated genes (ISGs). Altogether, we summarize the relationship between glycolysis, antiviral immunity, and lncRNAs and propose that lncRNAs interact with glycolysis and antiviral pathways, providing a new perspective for the future treatment against virus infection, including SARS-CoV-2.

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Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection

Cited by 86 publications

References 76 publications

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair

The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis

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