Sex differences in inflammation, redox biology, mitochondria and autoimmunity

Florio, Damian N. Di; Sin, Jon; Coronado, Michael; Atwal, Paldeep S.; Fairweather, De Lisa

doi:10.1016/j.redox.2020.101482

Cited by 108 publications

(86 citation statements)

References 155 publications

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“…Sex differences in immune response have been noted in literature, although the reasons are not clear. Males experience greater severity and prevalence of bacterial, viral, fungal and parasitic infections than females, who also mount a more robust response to antigenic challenges including infection and vaccination [75][76][77][78]. We (Davis et al) have used machine learning approaches to identify a cluster of genes involved in lipid biosynthesis, previously shown to be upregulated by testosterone, which correlates with poor virus-neutralizing activity in men [79].…”

Section: Host-specific Variations In Covid-19 Immune Responsementioning

confidence: 99%

Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response

et al. 2020

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Purpose of Review Coronavirus disease of 2019 (COVID-19) is a cause of significant morbidity and mortality worldwide. While cardiac injury has been demonstrated in critically ill COVID-19 patients, the mechanism of injury remains unclear. Here, we review our current knowledge of the biology of SARS-CoV-2 and the potential mechanisms of myocardial injury due to viral toxicities and host immune responses. Recent Findings A number of studies have reported an epidemiological association between history of cardiac disease and worsened outcome during COVID infection. Development of new onset myocardial injury during COVID-19 also increases mortality. While limited data exist, potential mechanisms of cardiac injury include direct viral entry through the angiotensinconverting enzyme 2 (ACE2) receptor and toxicity in host cells, hypoxia-related myocyte injury, and immune-mediated cytokine release syndrome. Potential treatments for reducing viral infection and excessive immune responses are also discussed. Summary COVID patients with cardiac disease history or acquire new cardiac injury are at an increased risk for in-hospital morbidity and mortality. More studies are needed to address the mechanism of cardiotoxicity and the treatments that can minimize permanent damage to the cardiovascular system.

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Section: Host-specific Variations In Covid-19 Immune Responsementioning

confidence: 99%

Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response

et al. 2020

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“…Several and specific interleukins (ILs), including IL‐2, IL‐6, and tumor necrosis factor (TNF)–alpha, and chemokines are markedly up‐regulated in patients displaying a serious pulmonary involvement or requiring intensive care with a poor long‐term prognosis 100,101 . Despite the fact that the so‐called “immunocompetence handicap hypothesis” in men still remains debated, 102 differences in circulating sexual hormones levels may condition a gender‐related response to infections 103 . In fact, T exhibits modulating effects on the immune system that may potentially predispose men to different clinical course and prognosis in case of infectious diseases 104 .…”

Section: Resultsmentioning

confidence: 99%

Worse progression of COVID‐19 in men: Is testosterone a key factor?

et al. 2020

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Background The novel severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) disease 2019 (COVID‐19) seems to have a worse clinical course among infected men compared with women, thus highlighting concerns about gender predisposition to serious prognosis. Therefore, androgens, particularly testosterone (T), could be suspected as playing a critical role in driving this excess of risk. However, gonadal function in critically ill men is actually unknown, mainly because serum T concentration is not routinely measured in clinical practice, even more in this clinical context. Objective To overview on possible mechanisms by which serum T levels could affect the progression of COVID‐19 in men. Methods Authors searched PubMed/MEDLINE, Web of Science, EMBASE, Cochrane Library, Google, and institutional websites for medical subject headings terms and free text words referred to “SARS‐CoV‐2,” “COVID‐19,” “testosterone,” “male hypogonadism,” “gender” “immune system,” “obesity,” “thrombosis” until May 19th 2020. Results T, co‐regulating the expression of angiotensin‐converting enzyme 2 and transmembrane protease serine 2 in host cells, may facilitate SARS‐CoV‐2 internalization. Instead, low serum T levels may predispose to endothelial dysfunction, thrombosis and defective immune response, leading to both impaired viral clearance and systemic inflammation. Obesity, one of the leading causes of severe prognosis in infected patients, is strictly associated with functional hypogonadism, and may consistently strengthen the aforementioned alterations, ultimately predisposing to serious respiratory and systemic consequences. Discussion and conclusion T in comparison to estrogen may predispose men to a widespread COVID‐19 infection. Low serum levels of T, which should be supposed to characterize the hormonal milieu in seriously ill individuals, may predispose men, especially elderly men, to poor prognosis or death. Further studies are needed to confirm these pathophysiological assumptions and to promptly identify adequate therapeutic strategies.

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“…In a recent study, HMGB1 in LPS-induced acute lung injury caused proinflammatory polarization of macrophages through the binding of TLR-2 and TLR-4 which stimulate the protein kinase R (PKR) [77]. Large amounts of TLR-4 have been found in males, consequent to testosterone production [78]. Testosterone induces DAMP release resulting in increased TLR4 signaling in males compared to females.…”

Section: Damage-associated Molecular Patterns (Damps) and Virus Infecmentioning

confidence: 99%

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

Cicco

Racanelli

et al. 2020

Mediators of Inflammation

144

148

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COVID-19 is a pandemic disease caused by the new coronavirus SARS-CoV-2 that mostly affects the respiratory system. The consequent inflammation is not able to clear viruses. The persistent excessive inflammatory response can build up a clinical picture that is very difficult to manage and potentially fatal. Modulating the immune response plays a key role in fighting the disease. One of the main defence systems is the activation of neutrophils that release neutrophil extracellular traps (NETs) under the stimulus of autophagy. Various molecules can induce NETosis and autophagy; some potent activators are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). This molecule is released by damaged lung cells and can induce a robust innate immunity response. The increase in HMGB1 and NETosis could lead to sustained inflammation due to SARS-CoV-2 infection. Therefore, blocking these molecules might be useful in COVID-19 treatment and should be further studied in the context of targeted therapy.

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Sex differences in inflammation, redox biology, mitochondria and autoimmunity

Cited by 108 publications

References 155 publications

Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response

Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response

Worse progression of COVID‐19 in men: Is testosterone a key factor?

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

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