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Cited by 186Viral Infections and Immunology ResearchInflammasome and immune disordersMitochondrial Function and Pathology

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Sex differences in inflammation, redox biology, mitochondria and autoimmunity

Open access
Di Florio, Damian N., Sin, Jon, Coronado, Michael J., Atwal, Paldeep S., Fairweather, DeLisa·2020·Redox Biology
DOI 10.1016/j.redox.2020.101482PMC PMC7212489
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Abstract

Autoimmune diseases are characterized by circulating antibodies and immune complexes directed against self-tissues that result in both systemic and organ-specific inflammation and pathology. Most autoimmune diseases occur more often in women than men. One exception is myocarditis, which is an inflammation of the myocardium that is typically caused by viral infections. Sex differences in the immune response and the role of the sex hormones estrogen and testosterone are well established based on animal models of autoimmune viral myocarditis as well as in mitochondrial function leading to reactive oxygen species production. RNA viruses like coxsackievirus B3, the primary cause of myocarditis in the US, activate the inflammasome through mitochondrial antiviral signaling protein located on the mitochondrial outer membrane. Toll-like receptor 4 and the inflammasome are the primary signaling pathways that increase inflammation during myocarditis, which is increased by testosterone. This review describes what is known about sex differences in inflammation, redox biology and mitochondrial function in the male-dominant autoimmune disease myocarditis and highlights gaps in the literature and future directions.

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Figures

Fig. 1 Proposed pathogenesis of coxsackievirus-induced myocarditis/DCM: After infection by fecal-oral transmission, coxsackievirus enters the gut where it replicates. When innate antiviral and self-damage immune signaling is initiated, dendritic cells that have captured viral antigen travel to the lymph nodes to activate T and B cells. Around day 2–3 after infection coxsackievirus causes viremia which allows it access to the heart. Activation of resident cardiac mast cell and macrophage populations increase monocyte trafficking. During peak myocarditis in males (around 10 days after infection) macrophages can comprise nearly 80% of the infiltrate in the heart with smaller numbers of T and B cells. After clearance of active viral infection around day 12–14 after infection immune cells in the heart quickly disappear. The immune response to the viral infection activates remodeling genes during myocarditis that over time can lead to cardiac remodeling, fibrosis and cardiac dilatation. Patients are at risk of sudden cardiac death during myocarditis and those that survive can develop dilated cardiomyopathy and chronic heart failure that may require a heart transplant.
Fig. 1 Proposed pathogenesis of coxsackievirus-induced myocarditis/DCM: After infection by fecal-oral transmission, coxsackievirus enters the gut where it replicates. When innate antiviral and self-damage immune signaling is initiated, dendritic cells that have captured viral antigen travel to the lymph nodes to activate T and B cells. Around day 2–3 after infection coxsackievirus causes viremia which allows it access to the heart. Activation of resident cardiac mast cell and macrophage populations increase monocyte trafficking. During peak myocarditis in males (around 10 days after infection) macrophages can comprise nearly 80% of the infiltrate in the heart with smaller numbers of T and B cells. After clearance of active viral infection around day 12–14 after infection immune cells in the heart quickly disappear. The immune response to the viral infection activates remodeling genes during myocarditis that over time can lead to cardiac remodeling, fibrosis and cardiac dilatation. Patients are at risk of sudden cardiac death during myocarditis and those that survive can develop dilated cardiomyopathy and chronic heart failure that may require a heart transplant.CC BY-NC-ND · PubMed Central
Fig. 2 Sex differences in the immune response in myocarditis/DCM: Females (top, pink) have low levels of cardiac inflammation during myocarditis due to an elevated anti-inflammatory immune response that is characterized by higher numbers of Th2-type immune cells, an M2 (anti-inflammatory) macrophage phenotype, greater numbers of Foxp3+ regulatory T cells, and higher levels of anti-inflammatory cytokines like IL-4 and IL-10. In contrast, males (bottom, blue) produce a robust proinflammatory immune response during myocarditis that is characterized by mast cell activation, greater numbers of macrophages that express a more M1 phenotype, and elevated proinflammatory cytokines that release IL-1β, IL-18, and IL-6 that stimulates Th17 cells, which promote remodeling and fibrosis that leads to DCM. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2 Sex differences in the immune response in myocarditis/DCM: Females (top, pink) have low levels of cardiac inflammation during myocarditis due to an elevated anti-inflammatory immune response that is characterized by higher numbers of Th2-type immune cells, an M2 (anti-inflammatory) macrophage phenotype, greater numbers of Foxp3+ regulatory T cells, and higher levels of anti-inflammatory cytokines like IL-4 and IL-10. In contrast, males (bottom, blue) produce a robust proinflammatory immune response during myocarditis that is characterized by mast cell activation, greater numbers of macrophages that express a more M1 phenotype, and elevated proinflammatory cytokines that release IL-1β, IL-18, and IL-6 that stimulates Th17 cells, which promote remodeling and fibrosis that leads to DCM. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)CC BY-NC-ND · PubMed Central
Fig. 3 Proposed model of sex differences in ROS during myocarditis.① Increased ER activation due to higher estrogen in females leads to ② a profusion phenotype during myocarditis, whereas lower ER signaling in males during myocarditis leads to ③ increased mitochondrial fission. ④ Profusion mitochondrial phenotype in females decreases ROS while anti-oxidants neutralize excess ROS produced by NOX. In males, mitochondrial fission contributes to higher ROS while also releasing mitophagy-associated DAMPs (as mitochondrial fusion can be a precursor to mitophagy under cellular stress conditions such as infection) which can activate the inflammasome. ⑤ Increased TLR4 signaling in males compared to females leads to higher proIL-1β and proIL-18 which are cleaved by activated caspase-1 ⑥ to the active forms IL-1β and IL-18. ⑦ More inflammasome activation occurs in males due to increased intracellular ROS with higher IFNγ signaling compared to females. ⑧ Elevated IL-4 in females promotes a cardioprotective immune response comprised of anti-inflammatory Th2 CD4+ T cells and regulatory M2 macrophages while in males elevated IL-18 and IFNγ promote a proinflammatory immune phenotype resulting in M1 macrophages and Th1 CD4+ T cells.
Fig. 3 Proposed model of sex differences in ROS during myocarditis.① Increased ER activation due to higher estrogen in females leads to ② a profusion phenotype during myocarditis, whereas lower ER signaling in males during myocarditis leads to ③ increased mitochondrial fission. ④ Profusion mitochondrial phenotype in females decreases ROS while anti-oxidants neutralize excess ROS produced by NOX. In males, mitochondrial fission contributes to higher ROS while also releasing mitophagy-associated DAMPs (as mitochondrial fusion can be a precursor to mitophagy under cellular stress conditions such as infection) which can activate the inflammasome. ⑤ Increased TLR4 signaling in males compared to females leads to higher proIL-1β and proIL-18 which are cleaved by activated caspase-1 ⑥ to the active forms IL-1β and IL-18. ⑦ More inflammasome activation occurs in males due to increased intracellular ROS with higher IFNγ signaling compared to females. ⑧ Elevated IL-4 in females promotes a cardioprotective immune response comprised of anti-inflammatory Th2 CD4+ T cells and regulatory M2 macrophages while in males elevated IL-18 and IFNγ promote a proinflammatory immune phenotype resulting in M1 macrophages and Th1 CD4+ T cells.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Di Florio, D. N., Sin, J., Coronado, M. J., Atwal, P. S., & Fairweather, D.
Affiliations
  • Cedars-Sinai Medical Center (US)
  • Whitman College (US)
  • Mayo Clinic (US)
Corresponding author
Fairweather, DeLisa
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2020-04
Volume
31
Pages
101482
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2020.101482
PMC
PMC7212489
OpenAlex
W3010344840
Cited by
185
References
164
Citations by year
2026: 30 · 2025: 24 · 2024: 26 · 2023: 44 · 2022: 29 · 2021: 19 · 2020: 12
FWCI
4.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Mayo Clinic
  • National Institutes of Health (R21 AI145356, R21 AI152318, TL1 TR002380)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Viral Infections and Immunology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
sex differences, autoimmune myocarditis, viral myocarditis, coxsackievirus B3, inflammasome, TLR4, reactive oxygen species, mitochondrial function, estrogen, testosterone, inflammation, autoimmunity
MeSH terms
Animals, Autoimmune Diseases, Biology, Disease Models, Animal, Female, Humans, Inflammation, Male, Mitochondria, Myocardium, Oxidation-Reduction, Sex Characteristics, Autoimmunity

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