Sex-specific stress response and HMGB1 release in pulmonary endothelial cells

Zemskova, Marina; Kurdyukov, Sergey; James, Joel; McClain, Nolan; Rafikov, Ruslan; Rafikova, Olga

doi:10.1371/journal.pone.0231267

Cited by 35 publications

(32 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sex-related differences in immune responses can lead to differential mode of action to clear the viral load and damaged cells. Stressed pulmonary endothelial cells in males are known to undergo necrosis while in females apoptosis is more common [71]. Since necrosis releases more HMGB1 than apoptosis [71], this indicates that HMGB1 levels are differentially regulated in male and female COVID-19 patients with higher levels in males that further contributes to the severity and high mortality in males.…”

Section: Immune System Differences and Viral Infectionmentioning

confidence: 99%

Sex differences in severity and mortality from COVID-19: are males more vulnerable?

2020

View full text Add to dashboard Cite

Coronavirus disease 2019 (COVID-19) has shown high infection and mortality rates all over the world, and despite the global efforts, there is so far no specific therapy available for COVID-19. Interestingly, while the severity and mortality of COVID-19 are higher in males than in females, the underlying molecular mechanisms are unclear. In this review, we explore sex-related differences that may be contributing factors to the observed male-biased mortality from COVID-19. Males are considered the weaker sex in aspects related to endurance and infection control. Studies show that viral RNA clearance is delayed in males with COVID-19. A recent study has indicated that the testis can harbor coronavirus, and consequently, males show delayed viral clearance. However, the role of testis involvement in COVID-19 severity and mortality needs further research. Males and females show a distinct difference in immune system responses with females eliciting stronger immune responses to pathogens. This difference in immune system responses may be a major contributing factor to viral load, disease severity, and mortality. In addition, differences in sex hormone milieus could also be a determinant of viral infections as estrogen has immunoenhancing effects while testosterone has immunosuppressive effects. The sex-specific severity of COVID-19 infections indicates that further research on understanding the sex differences is needed. Inclusion of both males and females in basic research and clinical trials is required to provide critical information on sex-related differences that may help to better understand disease outcome and therapy.

show abstract

Section: Immune System Differences and Viral Infectionmentioning

confidence: 99%

Sex differences in severity and mortality from COVID-19: are males more vulnerable?

2020

View full text Add to dashboard Cite

show abstract

“…A recent study demonstrated an unexpected genderspecific stress response and HMGB1 release in isolated murine pulmonary endothelial cells (Zemskova et al 2020). These cells from males were more sensitive than those from females to hypoxia and impaired mitochondrial function to which they responded by necrotic death.…”

Section: Introductionmentioning

confidence: 99%

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Andersson

Ottestad

Tracey

2020

Mol Med

204

212

View full text Add to dashboard Cite

Background: The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males.Conclusion: Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.

show abstract

“…This suggests that P. falciparum parasites or parasite products trigger signalling pathways in innate immune cells from females but not males. It is known that the necrotic or necroptotic pathway of cell death which results in the release of HGMB1 by dying cells occurs only in females (23). The relevance of this mechanism to our findings in Ugandan infants with malaria remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in concentrations of HMGB1 and numbers of pigmented monocytes in infants with malaria

Kanoi

Egwang²

2021

Preprint

View full text Add to dashboard Cite

Females generally mount more robust innate and adaptive immune responses and demonstrate a higher rate of morbidity, and prevalence of autoimmune diseases by comparison with males. In malaria, females demonstrate higher concentrations of antibodies and rates of severe adverse events and mortality following natural infections and malaria vaccination. Although monocytes/macrophages play a crucial role in disease and protection in malaria, no studies have investigated sex differences in their functions in production of proinflammatory cytokines and chemokines in malaria-infected subjects. Here, we show significant sex differences in serum concentrations of HMGB1, a non-histone chromatin-associated protein, and numbers of pigmented monocytes, which are both markers of severe malaria, in infants <5 years old from a malaria endemic region in Northern Uganda. Female infants with clinical malaria had significantly higher HMGB1 concentrations than male infants, and female infants with asymptomatic malaria had significantly lower numbers of pigmented monocytes than male infants with asymptomatic malaria. There was (1) a significant correlation between HMGB1 concentrations and pigmented monocyte numbers in female but not male infants; and (2) a significant correlation between HMGB1 concentrations and parasite densities in female but not male infants. These findings suggest that female infants with clinical malaria might be at a greater risk of morbidity characterized by higher serum HMGB1 levels.

show abstract

Sex-specific stress response and HMGB1 release in pulmonary endothelial cells

Cited by 35 publications

References 48 publications

Sex differences in severity and mortality from COVID-19: are males more vulnerable?

Sex differences in severity and mortality from COVID-19: are males more vulnerable?

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Sex differences in concentrations of HMGB1 and numbers of pigmented monocytes in infants with malaria

Contact Info

Product

Resources

About