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1.
Front Immunol ; 13: 999233, 2022.
Article in English | MEDLINE | ID: covidwho-2109767

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease-19 (COVID-19). The spike protein (S) of SARS-CoV-2 plays a crucial role in mediating viral infectivity; hence, in an extensive effort to curb the pandemic, many urgently approved vaccines rely on the expression of the S protein, aiming to induce a humoral and cellular response to protect against the infection. Given the very limited information about the effects of intracellular expression of the S protein in host cells, we aimed to characterize the early cellular transcriptomic changes induced by expression of the S protein in THP-1-derived macrophage-like cells. Results showed that a wide variety of genes were differentially expressed, products of which are mainly involved in cell adhesion, homeostasis, and most notably, antiviral and immune responses, depicted by significant downregulation of protocadherins and type I alpha interferons (IFNAs). While initially, the levels of IFNAs were higher in the medium of S protein expressing cells, the downregulation observed on the transcriptomic level might have been reflected by no further increase of IFNA cytokines beyond the 5 h time-point, compared to the mock control. Our study highlights the intrinsic pathogenic role of the S protein and sheds some light on the potential drawbacks of its utilization in the context of vaccination strategies.


Subject(s)
COVID-19 , Interferon Type I , Humans , Spike Glycoprotein, Coronavirus , SARS-CoV-2 , Antiviral Agents/pharmacology , Protocadherins , Immunity , Macrophages/metabolism
2.
J Leukoc Biol ; 112(3): 569-576, 2022 09.
Article in English | MEDLINE | ID: covidwho-2047706

ABSTRACT

Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV2), which causes the disease COVID-19, has caused an unprecedented global pandemic. Angiotensin-converting enzyme 2 (ACE2) is the major cellular receptor for SARS-CoV2 entry, which is facilitated by viral Spike priming by cellular TMPRSS2. Macrophages play an important role in innate viral defense and are also involved in aberrant immune activation that occurs in COVID-19, and thus direct macrophage infection might contribute to severity of SARS-CoV2 infection. Here, we demonstrate that monocytes and monocyte-derived macrophages (MDM) under in vitro conditions express low-to-undetectable levels of ACE2 and TMPRSS2 and minimal coexpression. Expression of these receptors remained low in MDM induced to different subtypes such as unpolarized, M1 and M2 polarized. Untreated, unpolarized, M1 polarized, and M2 polarized MDM were all resistant to infection with SARS-CoV2 pseudotyped virions. These findings suggest that direct infection of myeloid cells is unlikely to be a major mechanism of SARS-CoV2 pathogenesis. Summary sentence: Monocytes and macrophages express minimal ACE2 and TMPRSS2 and resist SARS-CoV-2 Spike-mediated infection, suggesting direct myeloid cell infection is unlikely a major contributor to pathogenesis.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Macrophages , Monocytes , Serine Endopeptidases , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , Disease Resistance , Humans , Macrophages/metabolism , Macrophages/virology , Monocytes/metabolism , Monocytes/virology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , RNA, Viral , SARS-CoV-2 , Serine Endopeptidases/metabolism
3.
Int J Mol Sci ; 23(17)2022 Aug 26.
Article in English | MEDLINE | ID: covidwho-2023746

ABSTRACT

Although interstitial lung disease (ILD) is a life-threatening pathological condition that causes respiratory failure, the efficiency of current therapies is limited. This study aimed to investigate the effects of human MIKO-1 (hMIKO-1), a hybrid protein that suppresses the abnormal activation of macrophages, on murine macrophage function and its therapeutic effect in a mouse model of bleomycin-induced ILD (BLM-ILD). To this end, the phenotype of thioglycolate-induced murine peritoneal macrophages co-cultured with hMIKO-1 was examined. The mice were assigned to normal, BLM-alone, or BLM + hMIKO-1 groups, and hMIKO-1 (0.1 mg/mouse) was administered intraperitoneally from day 0 to 14. The mice were sacrificed on day 28, and their lungs were evaluated by histological examination, collagen content, and gene expression levels. hMIKO-1 suppressed the polarization of murine macrophages to M2 predominance in vitro. The fibrosis score of lung pathology and lung collagen content of the BLM + hMIKO-1 group were significantly lower than those in the BLM-alone group. The expression levels of TNF-α, IL-6, IL-1ß, F4/80, and TIMP-1 in the lungs of the BLM + hMIKO-1 group were significantly lower than those in the BLM-alone group. These findings indicate that hMIKO-1 reduces lung fibrosis and may be a future therapeutic candidate for ILD treatment.


Subject(s)
Lung Diseases, Interstitial , Pulmonary Fibrosis , Animals , Bleomycin/toxicity , Collagen/metabolism , Disease Models, Animal , Humans , Lung/pathology , Lung Diseases, Interstitial/chemically induced , Lung Diseases, Interstitial/drug therapy , Lung Diseases, Interstitial/metabolism , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism
4.
PLoS One ; 17(8): e0273500, 2022.
Article in English | MEDLINE | ID: covidwho-2002334

ABSTRACT

BACKGROUND AND OBJECTIVE: A cytokine storm is caused by inflammatory cells, including pro-inflammatory macrophage phenotype (M1), and play a critical role in the pathogenesis of COVID-19, in which diffuse alveolar damage occurs in the lungs due to oxidative stress exposure. Heme oxygenase (HO)-1 is a stress-induced protein produced by the anti-inflammatory / anti-oxidative macrophage phenotype (M2), which also produces soluble CD163 (sCD163). In our study, we investigated and determined that serum HO-1 can be a predictive biomarker for assessing both the severity and the outcome of COVID-19 patients. METHOD: The serum concentrations of HO-1 and sCD163 of COVID-19 patients were measured on admission. The relationship between these biomarkers and other clinical parameters and outcomes were evaluated. RESULTS: Sixty-four COVID-19 patients (11 mild, 38 moderate, and 15 severe cases) were assessed. The serum HO-1 tended to increase (11.0 ng/mL vs. 24.3 ng/mL vs. 59.6 ng/mL with severity). Serum HO-1 correlated with serum lactate dehydrogenase (R = 0.422), C-reactive protein (R = 0.463), and the ground glass opacity (GGO) and consolidation score (R = 0.625) of chest computed tomography. The serum HO-1 showed a better area under the curve (AUC) for predicting ICU admission than the serum sCD163 (HO-1; 0.816 and sCD163; 0.743). In addition, composite parameters including serum HO-1 and the GGO and consolidation score showed a higher AUC for predicting ICU admission than the AUC of a single parameter. CONCLUSION: Clinically, serum HO-1, reflecting the activation of M2, could be a very useful marker for evaluating disease severity and predicting prognoses for COVID-19 patients. In addition, controlling activated M2 might be a preventative COVID-19 therapeutic target.


Subject(s)
COVID-19 , Heme Oxygenase-1/metabolism , Biomarkers , Humans , Macrophages/metabolism , Prognosis
5.
Int J Mol Sci ; 23(15)2022 Jul 26.
Article in English | MEDLINE | ID: covidwho-1994077

ABSTRACT

The gut barrier is a single cell layer that separates gut micro-organisms from the host, and gut permeability defects result in the translocation of microbial molecules from the gut into the blood. Despite the silent clinical manifestation, gut translocation of microbial molecules can induce systemic inflammation that might be an endogenous exacerbating factor of systemic lupus erythematosus. In contrast, circulatory immune-complex deposition and the effect of medications on the gut, an organ with an extremely large surface area, of patients with active lupus might cause gut translocation of microbial molecules, which worsens lupus severity. Likewise, the imbalance of gut microbiota may initiate lupus and/or interfere with gut integrity which results in microbial translocation and lupus exacerbation. Moreover, immune hyper-responsiveness of innate immune cells (macrophages and neutrophils) is demonstrated in a lupus model from the loss of inhibitory Fc gamma receptor IIb (FcgRIIb), which induces prominent responses through the cross-link between activating-FcgRs and innate immune receptors. The immune hyper-responsiveness can cause cell death, especially apoptosis and neutrophil extracellular traps (NETosis), which possibly exacerbates lupus, partly through the enhanced exposure of the self-antigens. Leaky gut monitoring and treatments (such as probiotics) might be beneficial in lupus. Here, we discuss the current information on leaky gut in lupus.


Subject(s)
Autoimmune Diseases , Lupus Erythematosus, Systemic , Humans , Immunity, Innate , Macrophages/metabolism , Neutrophils/metabolism
6.
Biochem Pharmacol ; 204: 115210, 2022 10.
Article in English | MEDLINE | ID: covidwho-1982612

ABSTRACT

In this review it is attempted to summarize current studies about formation of eicosanoids and other oxylipins in different human macrophages. There are several reports on M1 and M2 cells, also other phenotypes have been described. The eicosanoids formed in the largest amounts are the COX products TxB2 and PGE2. Thus shortlived bioactive TxA2 is a dominating product both in M1- and in M2-lineages, one exception seems to be MGM-CSF, TGFß cells. 5-LOX products are produced in both M1 and M2 macrophages, as well as in not fully polarized cells of both lineages. MM-CSF as well as M2 macrophages produced LTC4 more readily compared to M1 lineage cells. In MGM-CSF, TGFß cells LTB4 is a major eicosanoid, in line with high expression of LTA4 hydrolase. Recent reports described increased formation of leukotrienes in macrophages subjected to trained immunity with inflammatory transcriptional reprogramming. Also in macrophages derived from monocytes collected from post-COVID-19 patients. 15-LOX-1 is strongly upregulated in CD206+ M2 cells (M2a), differentiated in presence of IL-4. These macrophages also express 15-LOX-2. In incubations with pathogenic E. coli as well as other stimuli 15(S)-HETE and 17(S)-HDHA were major oxylipins formed. Also, the SPM precursor 5,15-diHETE and the SPM RvD5 were produced in considerable amounts, while other SPMs were less abundant. In M2 macrophages incubated with E. coli or S. aureus the cytosolic 15-LOX-1 enzyme accumulated to punctuate structures in a Ca2+ dependent manner with a relatively slow time course, leading to formation of mediators from endogenous substrate. Chalcones, flavone-like anti-inflammatory natural products, induced translocation of 15-LOX-1 in M2 cells, with high formation of 15-LOX derived oxylipins.


Subject(s)
Biological Products , Eicosanoids , Macrophages , Oxylipins , Arachidonate 5-Lipoxygenase/metabolism , Biological Products/metabolism , COVID-19 , Chalcones , Cyclooxygenase 2/metabolism , Eicosanoids/metabolism , Escherichia coli/metabolism , Flavones , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Hydrolases/metabolism , Hydroxyeicosatetraenoic Acids/metabolism , Interleukin-4/metabolism , Leukotrienes , Macrophage Colony-Stimulating Factor , Macrophages/metabolism , Oxylipins/metabolism , Prostaglandins E/metabolism , Scavenger Receptors, Class E/metabolism , Staphylococcus aureus , Transforming Growth Factor beta/metabolism
7.
Biomed Pharmacother ; 153: 113414, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1936094

ABSTRACT

Targeting macrophage M1 polarization is a promising strategy with fewer detrimental effects in COVID-19 curation. Phenylethanoid glycosides (PhGs) of Cistanche tubulosa are a botanical drug to possess various anti-inflammation-related functions, such as immunomodulating, hepatoprotective or neuroprotective functions, whereas their anti-inflammatory activity is rarely understood. A search into their anti-inflammatory characteristics led to the isolation of 49 PhGs along with 15 new PhGs. Their inhibitory effects against M1 polarization induced by LPS plus IFN-γ were explored in RAW264.7 macrophages. Of these PhGs, tubuloside B (Tub B) exerted substantial NO scavenging effect both in chemical- and cell-based assays, and it inhibited massive production of cytokines and chemokines. Tub B decreased ERK1/2 phosphorylation via direct binding and inhibited the MAPK signaling pathway. Tub B also directly binded to Mob1 protein, thereby increased the stability and level of Mob1 protein by inhibiting ubiquitinated degradation. Mob1 was pivotal for the anti-inflammatory activity of Tub B, and it acted independently of the canonical Hippo-YAP pathway. Moreover, ERK1/2 and Mob1 also had a synergic effect on modulating the inflammatory response. Finally, these effects of Tub B were verified in mice with LPS-induced systemic inflammatory response syndrome. Taken together, these results indicated that Tub B acted as a promising agent against M1 macrophage activation by synergistically targeting ERK1/2 and Mob1, and that it may potentially be a drug candidate to prevent/treat inflammatory diseases, especially in COVID-19.


Subject(s)
COVID-19 , Cistanche , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Glucosides , Glycosides/pharmacology , Intracellular Signaling Peptides and Proteins/metabolism , Lipopolysaccharides/metabolism , Lipopolysaccharides/pharmacology , MAP Kinase Signaling System , Macrophage Activation , Macrophages/metabolism , Mice , Plant Extracts/pharmacology
8.
Elife ; 112022 06 06.
Article in English | MEDLINE | ID: covidwho-1934562

ABSTRACT

COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV-2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppresses macrophage anti-inflammation and efficient tissue repair programs and provides mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.


Subject(s)
COVID-19 , SARS-CoV-2 , Anti-Inflammatory Agents/pharmacology , Apoptosis , Humans , Macrophages/metabolism , Phagocytosis
9.
Cell Mol Life Sci ; 79(6): 301, 2022 May 19.
Article in English | MEDLINE | ID: covidwho-1919756

ABSTRACT

Escalated innate immunity plays a critical role in SARS-CoV-2 pathology; however, the molecular mechanism is incompletely understood. Thus, we aim to characterize the molecular mechanism by which SARS-CoV-2 Spike protein advances human macrophage (MÏ´) inflammatory and glycolytic phenotypes and uncover novel therapeutic strategies. We found that human MÏ´s exposed to Spike protein activate IRAK4 phosphorylation. Blockade of IRAK4 in Spike protein-stimulated MÏ´s nullifies signaling of IRAK4, AKT, and baseline p38 without affecting ERK and NF-κB activation. Intriguingly, IRAK4 inhibitor (IRAK4i) rescues the SARS-CoV-2-induced cytotoxic effect in ACE2+HEK 293 cells. Moreover, the inflammatory reprogramming of MÏ´s by Spike protein was blunted by IRAK4i through IRF5 and IRF7, along with the reduction of monokines, IL-6, IL-8, TNFα, and CCL2. Notably, in Spike protein-stimulated MÏ´s, suppression of the inflammatory markers by IRAK4i was coupled with the rebalancing of oxidative phosphorylation over metabolic activity. This metabolic adaptation promoted by IRAK4i in Spike protein-activated MÏ´s was shown to be in part through constraining PFKBF3, HIF1α, cMYC, LDHA, lactate expression, and reversal of citrate and succinate buildup. IRAK4 knockdown could comparably impair Spike protein-enhanced inflammatory and metabolic imprints in human MÏ´s as those treated with ACE2, TLR2, and TLR7 siRNA. Extending these results, in murine models, where human SARS-CoV-2 Spike protein was not recognized by mouse ACE2, TLRs were responsible for the inflammatory and glycolytic responses instigated by Spike protein and were dysregulated by IRAK4i therapy. In conclusion, IRAK4i may be a promising strategy for severe COVID-19 patients by counter-regulating ACE2 and TLR-mediated MÏ´ hyperactivation. IRAK4i therapy counteracts MÏ´ inflammatory and glycolytic reprogramming triggered by Spike protein. This study illustrates that SARS-CoV-2 Spike protein activates IRAK4 signaling via ACE2 as well as TLR2 and TLR7 sensing in human MÏ´s. Remarkably, IRAK4i treatment can dysregulate both ACE-dependent and independent (via TLR sensing) SARS-CoV-2 Spike protein-activated inflammatory and metabolic imprints.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2 , Animals , HEK293 Cells , Humans , Interferon Regulatory Factors/metabolism , Interferon Regulatory Factors/pharmacology , Interleukin-1 Receptor-Associated Kinases/genetics , Interleukin-1 Receptor-Associated Kinases/metabolism , Macrophages/metabolism , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 7/metabolism
10.
Nutrients ; 14(13)2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1917652

ABSTRACT

Black rice is a functional food that is high in anthocyanin content, primarily C3G and P3G. It possesses nutraceutical properties that exhibit a range of beneficial effects on human health. Currently, the spike glycoprotein S1 subunit of SARS-CoV-2 (SP) has been reported for its contribution to pathological inflammatory responses in targeting lung tissue and innate immune cells during COVID-19 infection and in the long-COVID phenomenon. Our objectives focused on the health benefits of the C3G and P3G-rich fraction of black rice germ and bran (BR extract) on the inhibition of inflammatory responses induced by SP, as well as the inhibition of NF-kB activation and the NLRP3 inflammasome pathway in an in vitro model. In this study, BR extract was identified for its active anthocyanins, C3G and P3G, using the HPLC technique. A549-lung cells and differentiated THP-1 macrophages were treated with BR extract, C3G, or P3G prior to exposure to 100 ng/mL of SP. Their anti-inflammatory properties were then determined. BR extract at concentrations of 12.5-100 µg/mL exhibited anti-inflammation activity for both A549 and THP-1 cells through the significant suppression of NLRP3, IL-1ß, and IL-18 inflammatory gene expressions and IL-6, IL-1ß, and IL-18 cytokine secretions in a dose-dependent manner (p < 0.05). It was determined that both cell lines, C3G and P3G (at 1.25-10 µg/mL), were compatibly responsible for the significant inhibition of SP-induced inflammatory responses for both gene and protein levels (p < 0.05). With regard to the anti-inflammation mechanism, BR extract, C3G, and P3G could attenuate SP-induced inflammation via counteraction with NF-kB activation and downregulation of the inflammasome-dependent inflammatory pathway proteins (NLRP3, ASC, and capase-1). Overall, the protective effects of anthocyanins obtained from black rice germ and bran can be employed in potentially preventive strategies that use pigmented rice against the long-term sequelae of COVID-19 infection.


Subject(s)
COVID-19 , Oryza , Anthocyanins/pharmacology , COVID-19/complications , Glucosides/pharmacology , Humans , Inflammasomes , Interleukin-18 , Lung/metabolism , Macrophages/metabolism , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Oryza/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
11.
J Control Release ; 349: 118-132, 2022 09.
Article in English | MEDLINE | ID: covidwho-1914570

ABSTRACT

Cytokine storms are a primary cause of multiple organ damage and death after severe infections, such as SARS-CoV-2. However, current single cytokine-targeted strategies display limited therapeutic efficacy. Here, we report that peritoneal M2 macrophage-derived extracellular vesicles (M2-EVs) are multitarget nanotherapeutics that can be used to resolve cytokine storms. In detail, primary peritoneal M2 macrophages exhibited superior anti-inflammatory potential than immobilized cell lines. Systemically administered M2-EVs entered major organs and were taken up by phagocytes (e.g., macrophages). M2-EV treatment effectively reduced excessive cytokine (e.g., TNF-α and IL-6) release in vitro and in vivo, thereby attenuating oxidative stress and multiple organ (lung, liver, spleen and kidney) damage in endotoxin-induced cytokine storms. Moreover, M2-EVs simultaneously inhibited multiple key proinflammatory pathways (e.g., NF-κB, JAK-STAT and p38 MAPK) by regulating complex miRNA-gene and gene-gene networks, and this effect was collectively mediated by many functional cargos (miRNAs and proteins) in EVs. In addition to the direct anti-inflammatory role, human peritoneal M2-EVs expressed angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2 spike protein, and thus could serve as nanodecoys to prevent SARS-CoV-2 pseudovirus infection in vitro. As cell-derived nanomaterials, the therapeutic index of M2-EVs can be further improved by genetic/chemical modification or loading with specific drugs. This study highlights that peritoneal M2-EVs are promising multifunctional nanotherapeutics to attenuate infectious disease-related cytokine storms.


Subject(s)
Cytokine Release Syndrome , Extracellular Vesicles , Macrophages , MicroRNAs , Angiotensin-Converting Enzyme 2 , Animals , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines/metabolism , Endotoxins , Extracellular Vesicles/metabolism , Humans , Interleukin-6/metabolism , Macrophages/metabolism , MicroRNAs/metabolism , NF-kappa B/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases
12.
Sci Rep ; 12(1): 11078, 2022 06 30.
Article in English | MEDLINE | ID: covidwho-1908298

ABSTRACT

Immune cell chemotaxis to the sites of pathogen invasion is critical for fighting infection, but in life-threatening conditions such as sepsis and Covid-19, excess activation of the innate immune system is thought to cause a damaging invasion of immune cells into tissues and a consequent excessive release of cytokines, chemokines and neutrophil extracellular traps (NETs). In these circumstances, tempering excessive activation of the innate immune system may, paradoxically, promote recovery. Here we identify the antimalarial compound artemisinin as a potent and selective inhibitor of neutrophil and macrophage chemotaxis induced by a range of chemotactic agents. Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. Inhibition of SERCA3 by artemisinin was irreversible and was inhibited by iron chelation, suggesting iron-catalysed alkylation of a specific cysteine residue in SERCA3 as the mechanism by which artemisinin inhibits neutrophil motility. In murine infection models, artemisinin potently suppressed neutrophil invasion into both peritoneum and lung in vivo and inhibited the release of cytokines/chemokines and NETs. This work suggests that artemisinin may have value as a therapy in conditions such as sepsis and Covid-19 in which over-activation of the innate immune system causes tissue injury that can lead to death.


Subject(s)
Artemisinins , COVID-19 , Extracellular Traps , Macrophages , Neutrophils , Sepsis , Animals , Artemisinins/pharmacology , COVID-19/drug therapy , Calcium/metabolism , Calcium-Transporting ATPases/metabolism , Chemotaxis/drug effects , Cytokines/biosynthesis , Cytokines/metabolism , Extracellular Traps/metabolism , Macrophages/drug effects , Macrophages/metabolism , Mice , Neutrophils/drug effects , Neutrophils/metabolism , Thapsigargin/pharmacology
13.
Front Immunol ; 13: 863449, 2022.
Article in English | MEDLINE | ID: covidwho-1865450

ABSTRACT

The resolution of inflammation is a temporally and spatially coordinated process that in its innate manifestations, primarily involves neutrophils and macrophages. The shutdown of infection or injury-induced acute inflammation requires termination of neutrophil accumulation within the affected sites, neutrophil demise, and clearance by phagocytes (efferocytosis), such as tissue-resident and monocyte-derived macrophages. This must be followed by macrophage reprogramming from the inflammatory to reparative and consequently resolution-promoting phenotypes and the production of resolution-promoting lipid and protein mediators that limit responses in various cell types and promote tissue repair and return to homeostatic architecture and function. Recent studies suggest that these events, and macrophage reprogramming to pro-resolving phenotypes in particular, are not only important in the acute setting, but might be paramount in limiting chronic inflammation, autoimmunity, and various uncontrolled cytokine-driven pathologies. The SARS-CoV-2 (COVID-19) pandemic has caused a worldwide health and economic crisis. Severe COVID-19 cases that lead to high morbidity are tightly associated with an exuberant cytokine storm that seems to trigger shock-like pathologies, leading to vascular and multiorgan failures. In other cases, the cytokine storm can lead to diffuse alveolar damage that results in acute respiratory distress syndrome (ARDS) and lung failure. Here, we address recent advances on effectors in the resolution of inflammation and discuss how pro-resolution mechanisms with particular emphasis on macrophage reprogramming, might be harnessed to limit the universal COVID-19 health threat.


Subject(s)
COVID-19 , Inflammation , Macrophages , COVID-19/metabolism , COVID-19/pathology , Cytokine Release Syndrome , Cytokines/metabolism , Humans , Inflammation/metabolism , Macrophages/metabolism , SARS-CoV-2
14.
Int J Mol Sci ; 23(1)2021 Dec 23.
Article in English | MEDLINE | ID: covidwho-1855640

ABSTRACT

Macrophages are present in most human tissues and have very diverse functions. Activated macrophages are usually divided into two phenotypes, M1 macrophages and M2 macrophages, which are altered by various factors such as microorganisms, tissue microenvironment, and cytokine signals. Macrophage polarity is very important for infections, inflammatory diseases, and malignancies; its management can be key in the prevention and treatment of diseases. In this review, we assess the current state of knowledge on macrophage polarity and report on its prospects as a therapeutic target.


Subject(s)
Cell Polarity/physiology , Macrophages/pathology , Animals , Cytokines/metabolism , Disease , Humans , Macrophages/metabolism
15.
PLoS Pathog ; 18(5): e1010471, 2022 05.
Article in English | MEDLINE | ID: covidwho-1833668

ABSTRACT

The ability to treat severe viral infections is limited by our understanding of the mechanisms behind virus-induced immunopathology. While the role of type I interferons (IFNs) in early control of viral replication is clear, less is known about how IFNs can regulate the development of immunopathology and affect disease outcomes. Here, we report that absence of type I IFN receptor (IFNAR) is associated with extensive immunopathology following mucosal viral infection. This pathology occurred independent of viral load or type II immunity but required the presence of macrophages and IL-6. The depletion of macrophages and inhibition of IL-6 signaling significantly abrogated immunopathology. Tissue destruction was mediated by macrophage-derived matrix metalloproteinases (MMPs), as MMP inhibition by doxycycline and Ro 28-2653 reduced the severity of tissue pathology. Analysis of post-mortem COVID-19 patient lungs also displayed significant upregulation of the expression of MMPs and accumulation of macrophages. Overall, we demonstrate that IFNs inhibit macrophage-mediated MMP production to prevent virus-induced immunopathology and uncover MMPs as a therapeutic target towards viral infections.


Subject(s)
COVID-19 , Interferon Type I , Orthomyxoviridae Infections , Humans , Interleukin-6/metabolism , Macrophages/metabolism , Proteolysis
16.
Nature ; 606(7914): 585-593, 2022 06.
Article in English | MEDLINE | ID: covidwho-1815563

ABSTRACT

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA and a sustained interferon (IFN) response, all of which are recapitulated and required for pathology in the SARS-CoV-2-infected MISTRG6-hACE2 humanized mouse model of COVID-19, which has a human immune system1-20. Blocking either viral replication with remdesivir21-23 or the downstream IFN-stimulated cascade with anti-IFNAR2 antibodies in vivo in the chronic stages of disease attenuates the overactive immune inflammatory response, especially inflammatory macrophages. Here we show that SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release interleukin 1 (IL-1) and IL-18, and undergo pyroptosis, thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and the accompanying inflammatory response are necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Notably, this blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 through the production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.


Subject(s)
COVID-19 , Inflammasomes , Macrophages , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Animals , COVID-19/pathology , COVID-19/physiopathology , COVID-19/virology , Humans , Inflammasomes/metabolism , Interleukin-1 , Interleukin-18 , Lung/pathology , Lung/virology , Macrophages/metabolism , Macrophages/pathology , Macrophages/virology , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia/metabolism , Pneumonia/virology , Pyroptosis , Receptors, IgG , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity
17.
Genome Biol ; 23(1): 96, 2022 04 14.
Article in English | MEDLINE | ID: covidwho-1793837

ABSTRACT

Genome-wide association studies have identified 3p21.31 as the main risk locus for severe COVID-19, although underlying mechanisms remain elusive. We perform an epigenomic dissection of 3p21.31, identifying a CTCF-dependent tissue-specific 3D regulatory chromatin hub that controls the activity of several chemokine receptor genes. Risk SNPs colocalize with regulatory elements and are linked to increased expression of CCR1, CCR2 and CCR5 in monocytes and macrophages. As excessive organ infiltration of inflammatory monocytes and macrophages is a hallmark of severe COVID-19, our findings provide a rationale for the genetic association of 3p21.31 variants with elevated risk of hospitalization upon SARS-CoV-2 infection.


Subject(s)
COVID-19 , Monocytes , COVID-19/genetics , Genome-Wide Association Study , Humans , Macrophages/metabolism , Monocytes/metabolism , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , SARS-CoV-2
18.
Theranostics ; 12(6): 2639-2657, 2022.
Article in English | MEDLINE | ID: covidwho-1771696

ABSTRACT

Rationale: Macrophages are the frontline immune cells in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Angiotensin-converting enzyme 2 (ACE2) serves as the binding receptor to SARS-CoV-2 Spike glycoprotein for fusion and internalization into the human host cells. However, the mechanisms underlying SARS-CoV-2-elicited macrophage inflammatory responses remain elusive. Neutralizing SARS-CoV-2 by human ACE2 (hACE2) decoys has been proposed as a therapeutic approach to ameliorate SARS-CoV-2-stimulated inflammation. This study aims to investigate whether an engineered decoy receptor can abrogate SARS-CoV-2-induced macrophage inflammation. Methods: hACE2 was biotinylated to the surface of nano-liposomes (d = 100 nm) to generate Liposome-human ACE2 complex (Lipo-hACE2). Lentivirus expressing Spike protein (D614G) was also created as a pseudo-SARS-CoV-2 (Lenti-Spike). Liposome-hACE2 was used as a decoy receptor or competitive inhibitor to inhibit SARS-CoV-2 or Lenti-Spike-induced macrophage inflammation in vitro and in vivo. Results: Both SARS-CoV-2 and Lenti-Spike stimulated strong inflammatory responses by inducing the expression of key cytokine and chemokines, including IL-1ß, IL-6, TNFα, CCL-2, and CXCL-10, in murine and human macrophages in vitro, whereas Lipo-hACE2 decoy abolished these effects in macrophages. Furthermore, intravenous injection of Lenti-Spike led to increased macrophage and tissue inflammation in wild type mice, which was also abolished by Lipo-hACE2 treatment. Mechanistically, Spike protein stimulated macrophage inflammation by activating canonical NF-κB signaling. RNA sequencing analysis revealed that Lenti-Spike induced over 2,000 differentially expressed genes (DEGs) in murine macrophages, but deficiency of IκB kinase ß (IKKß), a key regulator for NF-κB activation, abrogated Lenti-Spike-elicited macrophage inflammatory responses. Conclusions: We demonstrated that the engineered Lipo-hACE2 acts as a molecular decoy to neutralize SARS-CoV-2 or Spike protein-induced inflammation in both murine and human macrophages, and activation of the canonical IKKß/NF-κB signaling is essential for SARS-CoV-2-elicited macrophage inflammatory responses.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2 , Animals , COVID-19/drug therapy , Humans , I-kappa B Kinase , Inflammation , Liposomes , Macrophages/metabolism , Mice , NF-kappa B/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
19.
Adv Biol (Weinh) ; 6(5): e2200007, 2022 May.
Article in English | MEDLINE | ID: covidwho-1706513

ABSTRACT

In humans, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause medical complications across various tissues and organs. Despite the advances to understanding the pathogenesis of SARS-CoV-2, its tissue tropism and interactions with host cells have not been fully understood. Existing clinical data have revealed disordered calcium and phosphorus metabolism in Coronavirus Disease 2019 (COVID-19) patients, suggesting possible infection or damage in the human skeleton system by SARS-CoV-2. Herein, SARS-CoV-2 infection in mouse models with wild-type and beta strain (B.1.351) viruses is investigated, and it is found that bone marrow-derived macrophages (BMMs) can be efficiently infected in vivo. Single-cell RNA sequencing (scRNA-Seq) analyses of infected BMMs identify distinct clusters of susceptible macrophages, including those related to osteoblast differentiation. Interestingly, SARS-CoV-2 entry on BMMs is dependent on the expression of neuropilin-1 (NRP1) rather than the widely recognized receptor angiotensin-converting enzyme 2 (ACE2). The loss of NRP1 expression during BMM-to-osteoclast differentiation or NRP1 neutralization and knockdown can significantly inhibit SARS-CoV-2 infection in BMMs. Importantly, it is found that authentic SARS-CoV-2 infection impedes BMM-to-osteoclast differentiation. Collectively, this study provides evidence for NRP1-mediated SARS-CoV-2 infection in BMMs and establishes a potential link between disturbed osteoclast differentiation and disordered skeleton metabolism in COVID-19 patients.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Humans , Macrophages/metabolism , Mice , Neuropilin-1/genetics , Osteoclasts/metabolism
20.
Front Immunol ; 13: 780839, 2022.
Article in English | MEDLINE | ID: covidwho-1686482

ABSTRACT

Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.


Subject(s)
Infections/immunology , Infections/metabolism , Macrophage Activation/immunology , Macrophages/immunology , Macrophages/metabolism , Animals , COVID-19/immunology , Humans , Immunity, Innate/immunology , SARS-CoV-2
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