Transcriptional, Epigenetic, and Functional Reprogramming of Monocytes From Non-Human Primates Following Chronic Alcohol Drinking
Chronic heavy drinking (CHD) of alcohol is a known risk factor for increased susceptibility to bacterial and viral infection as well as impaired wound healing. Evidence suggests that these defects are mediated by a dysregulated inflammatory response originating from myeloid cells, notably monocytes...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.724015/full |
| _version_ | 1818883900020097024 |
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| author | Sloan A. Lewis Sloan A. Lewis Suhas Sureshchandra Suhas Sureshchandra Brianna Doratt Brianna Doratt Vanessa A. Jimenez Cara Stull Kathleen A. Grant Ilhem Messaoudi Ilhem Messaoudi |
| author_facet | Sloan A. Lewis Sloan A. Lewis Suhas Sureshchandra Suhas Sureshchandra Brianna Doratt Brianna Doratt Vanessa A. Jimenez Cara Stull Kathleen A. Grant Ilhem Messaoudi Ilhem Messaoudi |
| author_sort | Sloan A. Lewis |
| collection | DOAJ |
| description | Chronic heavy drinking (CHD) of alcohol is a known risk factor for increased susceptibility to bacterial and viral infection as well as impaired wound healing. Evidence suggests that these defects are mediated by a dysregulated inflammatory response originating from myeloid cells, notably monocytes and macrophages, but the mechanisms remain poorly understood. Our ability to study CHD is impacted by the complexities of human drinking patterns and behavior as well as comorbidities and confounding risk factors for patients with alcohol use disorders. To overcome these challenges, we utilized a translational rhesus macaque model of voluntary ethanol self-administration that closely recapitulates human drinking patterns and chronicity. In this study, we examined the effects of CHD on blood monocytes in control and CHD female macaques after 12 months of daily ethanol consumption. While monocytes from CHD female macaques generated a hyper-inflammatory response to ex vivo LPS stimulation, their response to E. coli was dampened. In depth scRNA-Seq analysis of purified monocytes revealed significant shifts in classical monocyte subsets with accumulation of cells expressing markers of hypoxia (HIF1A) and inflammation (NFkB signaling pathway) in CHD macaques. The increased presence of monocyte subsets skewed towards inflammatory phenotypes was complemented by epigenetic analysis, which revealed higher accessibility of promoter regions that regulate genes involved in cytokine signaling pathways. Collectively, data presented in this manuscript demonstrate that CHD shifts classical monocyte subset composition and primes the monocytes towards a more hyper-inflammatory response to LPS, but compromised pathogen response. |
| first_indexed | 2024-12-19T15:40:59Z |
| format | Article |
| id | doaj.art-fe70796af6d342ed8d591f808c80ad89 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T15:40:59Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-fe70796af6d342ed8d591f808c80ad892022-12-21T20:15:28ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-08-011210.3389/fimmu.2021.724015724015Transcriptional, Epigenetic, and Functional Reprogramming of Monocytes From Non-Human Primates Following Chronic Alcohol DrinkingSloan A. Lewis0Sloan A. Lewis1Suhas Sureshchandra2Suhas Sureshchandra3Brianna Doratt4Brianna Doratt5Vanessa A. Jimenez6Cara Stull7Kathleen A. Grant8Ilhem Messaoudi9Ilhem Messaoudi10Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, United StatesInstitute for Immunology, University of California, Irvine, CA, United StatesDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA, United StatesInstitute for Immunology, University of California, Irvine, CA, United StatesDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA, United StatesInstitute for Immunology, University of California, Irvine, CA, United StatesOregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, United StatesOregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, United StatesOregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, United StatesDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA, United StatesInstitute for Immunology, University of California, Irvine, CA, United StatesChronic heavy drinking (CHD) of alcohol is a known risk factor for increased susceptibility to bacterial and viral infection as well as impaired wound healing. Evidence suggests that these defects are mediated by a dysregulated inflammatory response originating from myeloid cells, notably monocytes and macrophages, but the mechanisms remain poorly understood. Our ability to study CHD is impacted by the complexities of human drinking patterns and behavior as well as comorbidities and confounding risk factors for patients with alcohol use disorders. To overcome these challenges, we utilized a translational rhesus macaque model of voluntary ethanol self-administration that closely recapitulates human drinking patterns and chronicity. In this study, we examined the effects of CHD on blood monocytes in control and CHD female macaques after 12 months of daily ethanol consumption. While monocytes from CHD female macaques generated a hyper-inflammatory response to ex vivo LPS stimulation, their response to E. coli was dampened. In depth scRNA-Seq analysis of purified monocytes revealed significant shifts in classical monocyte subsets with accumulation of cells expressing markers of hypoxia (HIF1A) and inflammation (NFkB signaling pathway) in CHD macaques. The increased presence of monocyte subsets skewed towards inflammatory phenotypes was complemented by epigenetic analysis, which revealed higher accessibility of promoter regions that regulate genes involved in cytokine signaling pathways. Collectively, data presented in this manuscript demonstrate that CHD shifts classical monocyte subset composition and primes the monocytes towards a more hyper-inflammatory response to LPS, but compromised pathogen response.https://www.frontiersin.org/articles/10.3389/fimmu.2021.724015/fullalcoholinflammationmonocytesnonhuman primatesscRNA seqATAC-Seq |
| spellingShingle | Sloan A. Lewis Sloan A. Lewis Suhas Sureshchandra Suhas Sureshchandra Brianna Doratt Brianna Doratt Vanessa A. Jimenez Cara Stull Kathleen A. Grant Ilhem Messaoudi Ilhem Messaoudi Transcriptional, Epigenetic, and Functional Reprogramming of Monocytes From Non-Human Primates Following Chronic Alcohol Drinking Frontiers in Immunology alcohol inflammation monocytes nonhuman primates scRNA seq ATAC-Seq |
| title | Transcriptional, Epigenetic, and Functional Reprogramming of Monocytes From Non-Human Primates Following Chronic Alcohol Drinking |
| title_full | Transcriptional, Epigenetic, and Functional Reprogramming of Monocytes From Non-Human Primates Following Chronic Alcohol Drinking |
| title_fullStr | Transcriptional, Epigenetic, and Functional Reprogramming of Monocytes From Non-Human Primates Following Chronic Alcohol Drinking |
| title_full_unstemmed | Transcriptional, Epigenetic, and Functional Reprogramming of Monocytes From Non-Human Primates Following Chronic Alcohol Drinking |
| title_short | Transcriptional, Epigenetic, and Functional Reprogramming of Monocytes From Non-Human Primates Following Chronic Alcohol Drinking |
| title_sort | transcriptional epigenetic and functional reprogramming of monocytes from non human primates following chronic alcohol drinking |
| topic | alcohol inflammation monocytes nonhuman primates scRNA seq ATAC-Seq |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.724015/full |
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