Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection

Polcz, Valerie E; Barrios, Evan L; Chapin, Benjamin; Price, Catherine C.; Nagpal, Ravinder; Chakrabarty, Paramita; Casadesús, Gemma; Foster, Thomas C.; Moldawer, Lyle L.; Efron, Philip A.

doi:10.1042/cs20220555

Cited by 8 publications

(8 citation statements)

References 147 publications

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“…We started by determining LPS dose in C57BL/6J male mice from our facility (CEIB, IMIB, Murcia Spain). In the literature it has been described that males are more sensitive to LPS administration, therefore, we decided to test the appropriate LPS dose in males ( 30 , 36 ). At first, we looked at whether there was RGC loss 3 days after LPS administration.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, there is a sexual dimorphism in response to systemic inflammation in both patients and animal models (30)(31)(32)(33)(34)(35)(36). In fact, females usually have a better outcome.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, females usually have a better outcome. However, despite the increasing evidence of sexual dimorphisms in neurological and immunological systems, research into these differences in sepsis-associated neurodegeneration remains critically understudied ( 30 ).…”

Section: Introductionmentioning

confidence: 99%

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Retinal response to systemic inflammation differs between sexes and neurons

Rodríguez-Ramírez,

Norte-Muñoz,

Lucas-Ruiz

et al. 2024

Front. Immunol.

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BackgroundNeurological dysfunction and glial activation are common in severe infections such as sepsis. There is a sexual dimorphism in the response to systemic inflammation in both patients and animal models, but there are few comparative studies. Here, we investigate the effect of systemic inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) on the retina of male and female mice and determine whether antagonism of the NLRP3 inflammasome and the extrinsic pathway of apoptosis have protective effects on the retina.MethodsA single intraperitoneal injection of LPS (5 mg/kg) was administered to two months old C57BL/6J male and female mice. Retinas were examined longitudinally in vivo using electroretinography and spectral domain optical coherence tomography. Retinal ganglion cell (RGC) survival and microglial activation were analysed in flat-mounts. Retinal extracts were used for flow cytometric analysis of CD45 and CD11b positive cells. Matched plasma and retinal levels of proinflammatory cytokines were measured by ELISA. Retinal function and RGC survival were assessed in animals treated with P2X7R and TNFR1 antagonists alone or in combination.ResultsIn LPS-treated animals of both sexes, there was transient retinal dysfunction, loss of vision-forming but not non-vision forming RGCs, retinal swelling, microglial activation, cell infiltration, and increases in TNF and IL-1β. Compared to females, males showed higher vision-forming RGC death, slower functional recovery, and overexpression of lymphotoxin alpha in their retinas. P2X7R and TNFR1 antagonism, alone or in combination, rescued vision-forming RGCs. P2X7R antagonism also rescued retinal function. Response to treatment was better in females than in males.ConclusionsSystemic LPS has neuronal and sex-specific adverse effects in the mouse retina, which are counteracted by targeting the NLRP3 inflammasome and the extrinsic pathway of apoptosis. Our results highlight the need to analyse males and females in preclinical studies of inflammatory diseases affecting the central nervous system

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Retinal response to systemic inflammation differs between sexes and neurons

Rodríguez-Ramírez,

Norte-Muñoz,

Lucas-Ruiz

et al. 2024

Front. Immunol.

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“…Hormonal status of females contributes to variability in episodic memory on the watermaze and an age-related decline in episodic memory on the watermaze is linked to the decline in estradiol ( Warren and Juraska, 2000 ; Bean et al, 2014 ; Rentz et al, 2017 ). Furthermore, there may be a relationship between hormone levels and cell senescence which influences the effectiveness of treatments designed to preserve cognitive function ( Casaletto et al, 2020 ; Polcz et al, 2023 ). Therefore, prior to treatment, all 12-month animals were examined for estrus cycle.…”

Section: Methodsmentioning

confidence: 99%

Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging

Rani,

Bean,

Budamagunta

et al. 2024

Front. Aging Neurosci.

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There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats. Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the watermaze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.

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“…There are sex-based differences in the prognosis of sepsis, with women having a higher survival rate than men (9)(10)(11). A reason for this difference is the anti-inflammatory effect of female hormones.…”

Section: Introductionmentioning

confidence: 99%

Equol, a Soybean Metabolite With Estrogen-Like Functions, Decreases Lipopolysaccharide-Induced Human Neutrophil Extracellular Traps in Vitro

Murakami,

Ishikawa,

Higashi

et al. 2023

Shock

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Objective Neutrophil extracellular traps (NETs) defend against acute infections. However, their overexpression causes organ failure during sepsis. Control of NET formation may improve the outcomes of patients with sepsis. Equol, a soybean isoflavone, is a female hormone analog, which prevents inflammation. We evaluated the effects of equol on NET formation in human neutrophils during inflammatory stimulation in vitro. Methods Healthy volunteers provided blood samples. An enzyme-linked immunosorbent assay (ELISA) assessed serum equol concentrations. NET formation in neutrophils was induced by lipopolysaccharide (LPS) treatment. ELISA quantified DNA-binding elastase, and immunostaining assessed NET formation. Reverse-transcription quantitative PCR and western blotting detected G-protein-coupled receptor 30 (GPR30) or peptidyl arginine deiminase 4 (PAD4) expression. Flow cytometry assessed neutrophil phagocytic ability with inactivated Escherichia coli. Results In neutrophils derived from males with low-serum equol levels (low-serum equol group), equol significantly decreased DNA-binding elastase levels and NET formation. Equol did not decrease NETs in neutrophils from males with high-serum equol levels. GPR30 expression of neutrophils was higher in the low-serum than in the high-serum equol group. PAD4 mRNA levels and nuclear PAD4 protein expression also decreased than the vehicle control in the low-serum equol group. Equol did not alter the phagocytic ability of neutrophils. In neutrophils from young females, equol had no inhibitory effect on NET formation. Conclusions Equol decreases LPS-induced NET formation in neutrophils from males via inhibition of PAD4 expression. Our findings provide a rationale for investigating a new therapeutic approach using equol to control neutrophil activity during sepsis.

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Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection

Cited by 8 publications

References 147 publications

Retinal response to systemic inflammation differs between sexes and neurons

Retinal response to systemic inflammation differs between sexes and neurons

Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging

Equol, a Soybean Metabolite With Estrogen-Like Functions, Decreases Lipopolysaccharide-Induced Human Neutrophil Extracellular Traps in Vitro

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