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1.
Cell Death Differ ; 30(3): 742-752, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36307526

RESUMO

Macrophages are essential players for the host response against pathogens, regulation of inflammation and tissue regeneration. The wide range of macrophage functions rely on their heterogeneity and plasticity that enable a dynamic adaptation of their responses according to the surrounding environmental cues. Recent studies suggest that metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the metabolic pathways orchestrating macrophage activation are still under scrutiny. Optic atrophy 1 (OPA1) is a mitochondria-shaping protein controlling mitochondrial fusion, cristae biogenesis and respiration; clear evidence shows that the lack or dysfunctional activity of this protein triggers the accumulation of metabolic intermediates of the TCA cycle. In this study, we show that OPA1 has a crucial role in macrophage activation. Selective Opa1 deletion in myeloid cells impairs M1-macrophage commitment. Mechanistically, Opa1 deletion leads to TCA cycle metabolite accumulation and defective NF-κB signaling activation. In an in vivo model of muscle regeneration upon injury, Opa1 knockout macrophages persist within the damaged tissue, leading to excess collagen deposition and impairment in muscle regeneration. Collectively, our data indicate that OPA1 is a key metabolic driver of macrophage functions.


Assuntos
Mitocôndrias , Membranas Mitocondriais , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Transdução de Sinais , Macrófagos/metabolismo
2.
Cell Rep Med ; 4(11): 101266, 2023 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-37944530

RESUMO

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has fueled the COVID-19 pandemic with its enduring medical and socioeconomic challenges because of subsequent waves and long-term consequences of great concern. Here, we chart the molecular basis of COVID-19 pathogenesis by analyzing patients' immune responses at single-cell resolution across disease course and severity. This approach confirms cell subpopulation-specific dysregulation in COVID-19 across disease course and severity and identifies a severity-associated activation of the receptor for advanced glycation endproducts (RAGE) pathway in monocytes. In vitro THP1-based experiments indicate that monocytes bind the SARS-CoV-2 S1-receptor binding domain (RBD) via RAGE, pointing to RAGE-Spike interaction enabling monocyte infection. Thus, our results demonstrate that RAGE is a functional receptor of SARS-CoV-2 contributing to COVID-19 severity.


Assuntos
COVID-19 , Humanos , Monócitos , Pandemias , Receptor para Produtos Finais de Glicação Avançada/genética , SARS-CoV-2
3.
Viruses ; 14(3)2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35336973

RESUMO

Vaccination with an mRNA COVID-19 vaccine determines not only a consistent reduction in the risk of SARS-CoV-2 infection but also contributes to disease attenuation in infected people. Of note, hyperinflammation and damage-associated molecular patterns (DAMPs) have been clearly associated with severe illness and poor prognosis in COVID-19 patients. In this report, we revealed a significant reduction in the levels of IL-1ß and DAMPs molecules, as S100A8 and High Mobility Group Protein B1 (HMGB1), in vaccinated patients as compared to non-vaccinated ones. COVID-19 vaccination indeed prevents severe clinical manifestations in patients and limits the release of systemic danger signals in SARS-CoV-2 infected people.


Assuntos
COVID-19 , Vacinas Virais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , SARS-CoV-2 , Vacinação
4.
Front Immunol ; 12: 781352, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34950146

RESUMO

After the outburst of the SARS-CoV-2 pandemic, a worldwide research effort has led to the uncovering of many aspects of the COVID-19, among which we can count the outstanding role played by inflammatory cytokine milieu in the disease progression. Despite that, molecular mechanisms that regulate SARS-CoV-2 pathogenesis are still almost unidentified. In this study, we investigated whether the pro-inflammatory milieu of the host affects the susceptibility of SARS-CoV-2 infection by modulating ACE2 and TMPRSS2 expression. Our results indicated that the host inflammatory milieu favors SARS-CoV-2 infection by directly increasing TMPRSS2 expression. We unveiled the molecular mechanism that regulates this process and that can be therapeutically advantageously targeted.


Assuntos
Fator de Transcrição GATA2/metabolismo , Interleucina-1beta/metabolismo , SARS-CoV-2/patogenicidade , Serina Endopeptidases/metabolismo , Internalização do Vírus , Células A549 , COVID-19 , Humanos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
J Clin Med ; 10(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925921

RESUMO

Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disorder at high risk of arrhythmic sudden death in the young and athletes. AC is hallmarked by myocardial replacement with fibro-fatty tissue, favoring life-threatening cardiac arrhythmias and contractile dysfunction. The AC pathogenesis is unclear, and the disease urgently needs mechanism-driven therapies. Current AC research is mainly focused on 'desmosome-carrying' cardiomyocytes, but desmosomal proteins are also expressed by non-myocyte cells, which also harbor AC variants, including mesenchymal stromal cells (MSCs). Consistently, cardiac-MSCs contribute to adipose tissue in human AC hearts. We thus approached AC as a multicellular disorder, hypothesizing that it also affects extra-cardiac bone marrow (BM)-MSCs. Our results show changes in the desmosomal protein profile of both cardiac- and BM- MSCs, from desmoglein-2 (Dsg2)-mutant mice, accompanied with profound alterations in cytoskeletal organization, which are directly caused by AC-linked DSG2 downregulation. In addition, AC BM-MSCs display increased proliferation rate, both in vitro and in vivo, and, by using the principle of the competition homing assay, we demonstrated that mutant circulating BM-MSCs have increased propensity to migrate to the AC heart. Taken altogether, our results indicate that cardiac- and BM- MSCs are additional cell types affected in Dsg2-linked AC, warranting the novel classification of AC as a multicellular and multiorgan disease.

6.
Cell Death Dis ; 11(11): 957, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33159040

RESUMO

A global effort is currently undertaken to restrain the COVID-19 pandemic. Host immunity has come out as a determinant for COVID-19 clinical outcomes, and several studies investigated the immune profiling of SARS-CoV-2 infected people to properly direct the clinical management of the disease. Thus, lymphopenia, T-cell exhaustion, and the increased levels of inflammatory mediators have been described in COVID-19 patients, in particular in severe cases1. Age represents a key factor in COVID-19 morbidity and mortality2. Understanding age-associated immune signatures of patients are therefore important to identify preventive and therapeutic strategies. In this study, we investigated the immune profile of COVID-19 hospitalized patients identifying a distinctive age-dependent immune signature associated with disease severity. Indeed, defined circulating factors - CXCL8, IL-10, IL-15, IL-27, and TNF-α - positively correlate with older age, longer hospitalization, and a more severe form of the disease and may thus represent the leading signature in critical COVID-19 patients.


Assuntos
Infecções por Coronavirus/patologia , Citocinas/metabolismo , Pneumonia Viral/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , COVID-19 , Análise por Conglomerados , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Imunoglobulina G/sangue , Interleucina-10/metabolismo , Interleucina-8/metabolismo , Tempo de Internação , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , SARS-CoV-2 , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/metabolismo
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