Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2
| Autor: | Emily Barrett, Kevin Mangum, Sonya J. Wolf, Frank M. Davis, Andrea T. Obi, Christopher O. Audu, Xiaofeng Zhou, Monica Bame, Bethany B. Moore, Aaron denDekker, William J. Melvin, Sriganesh B Sharma, Katherine A. Gallagher, Amrita Joshi, Steven L. Kunkel, Alex Ruan |
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| Rok vydání: | 2021 |
| Předmět: |
Male
viruses medicine.medical_treatment Population coronavirus Inflammation medicine.disease_cause Mice Immunology and Inflammation medicine Macrophage Animals Humans education Coronavirus education.field_of_study Multidisciplinary Innate immune system diabetes epigenetics business.industry SARS-CoV-2 Macrophages NF-kappa B COVID-19 Histone-Lysine N-Methyltransferase Biological Sciences monocyte/macrophage medicine.disease Mice Inbred C57BL Cytokine Diabetes Mellitus Type 2 Immunology Increased inflammatory response Cytokines Female medicine.symptom Inflammation Mediators Cytokine storm business Coronavirus Infections Cytokine Release Syndrome Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance The COVID-19 pandemic has disproportionately affected patients with comorbidities, namely, obesity and type 2 diabetes. Macrophages (Mφs) are a key innate immune cell primarily responsible for the harmful, hyperinflammatory “cytokine storm” in patients that develop severe COVID-19. We describe a mechanism for this Mφ-mediated cytokine storm in response to coronavirus. In response to coronavirus infection, expression of the chromatin-modifying enzyme, SETDB2, decreases in Mφs, leading to increased transcription of inflammatory cytokines. Further, we find SETDB2 is regulated by an interferon beta (IFNβ)/JaK/STAT3 mechanism, and that exogenous administration of IFNβ can reverse inflammation, particularly in diabetic Mφs via an increase in SETDB2. Together, these results suggest therapeutic targeting of the IFNβ/SETDB2 axis in diabetic patients with COVID-19 may decrease pathologic inflammation. COVID-19 induces a robust, extended inflammatory “cytokine storm” that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNβ directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNβ reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNβ/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19. |
| Databáze: | OpenAIRE |
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