Monocyte Trafficking and Polarization Contribute to Sex Differences in Meta-Inflammation

Varghese, Mita; Clemente, Jeremy; Lerner, Arianna; Abrishami, Simin; Islam, M. Khyrul; Subbaiah, Perla; Singer, Kanakadurga

doi:10.3389/fendo.2022.826320

Cited by 16 publications

(18 citation statements)

References 74 publications

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“…Our findings are consistent with the previous literature suggesting that the immune response to pathogens or self-antigen differs in males and females 41 . This observation applies also to circulating monocytes in the context cardiovascular risk factors such as obesity 42 findings may provide potential mechanisms for why men have a higher prevalence of CVD than women in HIV patients 43 . Our findings imply that while mDll4 is a potential biomarker of systemic inflammation for both genders, exDll4 is more useful in males.…”

Section: Discussionmentioning

confidence: 87%

Monocyte-derived Dll4 is a novel contributor to persistent systemic inflammation in HIV patients

Wang

Singh

Yang

et al. 2023

Preprint

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Background: In people living with HIV (PLWH) on combination antiretroviral therapy (cART), persistent systemic inflammation is a driving force for the progression of comorbidities, such as cardiovascular and cerebrovascular diseases. In this context, monocyte- and macrophage-related inflammation rather than T cell activation is a major cause of chronic inflammation. However, the underlying mechanism of how monocytes cause persistent systemic inflammation in PLWH is elusive. Methods and Results: In vitro, we demonstrated that lipopolysaccharides (LPS) or tumor necrosis factor alpha (TNFα), induced a robust increase of Delta-like ligand 4 (Dll4) mRNA and protein expression in human monocytes and Dll4 secretion (extracellular Dll4, exDll4) from monocytes. Enhanced membrane-bound Dll4 (mDll4) expression in monocytes triggered Notch1 activation to promote pro-inflammatory factors expression. Dll4 silencing and inhibition of Nocth1 activation diminished the LPS or TNFα -induced inflammation. exDll4 releases in response to cytokines occurred in monocytes but not endothelial cells or T cells. In clinical specimens, we found that PLWH, both male and female, on cART, showed a significant increase in mDll4 expression, activation of Dll4-Notch1 signaling, and inflammatory markers in monocytes. Although there was no sex effect on mDII4 in PLWH, plasma exDll4 was significantly elevated in males but not females compared to HIV uninfected individuals. Furthermore, exDll4 plasma levels paralleled with monocytes mDll4 in male PLWH. Circulating exDll4 was also positively associated with pro-inflammatory monocytes phenotype and negatively associated with classic monocytes phenotype in male PLWH. Conclusion: Pro-inflammatory stimuli increase Dll4 expression and Dll4-Notch1 signaling activation in monocytes and enhance monocyte proinflammatory phenotype, contributing to persistent systemic inflammation in male and female PLWH. Therefore, monocyte mDll4 could be a potential biomarker and therapeutic target of systemic inflammation. Plasma exDll4 may also play an additional role in systemic inflammation but primarily in men.

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Section: Discussionmentioning

confidence: 87%

Monocyte-derived Dll4 is a novel contributor to persistent systemic inflammation in HIV patients

Wang

Singh

Yang

et al. 2023

Preprint

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“…Why female ATM proliferation is more prominent in males is unclear. It is possible that an increased proliferative capacity in female mice is related to suppression in obesity-induced adipose tissue inflammation compared to males 34 .…”

Section: Discussionmentioning

confidence: 99%

MSR1 is not required for obesity-associated inflammation and insulin resistance in mice

Nance

Muir

Delproprosto

et al. 2023

Sci Rep

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Obesity induces a chronic inflammatory state associated with changes in adipose tissue macrophages (ATMs). Macrophage scavenger receptor 1 (MSR1) has been implicated in the regulation of adipose tissue inflammation and diabetes pathogenesis; however, reports have been mixed on the contribution of MSR1 in obesity and glucose intolerance. We observed increased MSR1 expression in VAT of obese diabetic individuals compared to non-diabetic and single nuclear RNA sequencing identified macrophage-specific expression of MSR1 in human adipose tissue. We examined male Msr1−/− (Msr1KO) and WT controls and observed protection from obesity and AT inflammation in non-littermate Msr1KO mice. We then evaluated obese littermate Msr1+/− (Msr1HET) and Msr1KO mice. Both Msr1KO mice and Msr1HET mice became obese and insulin resistant when compared to their normal chow diet counterparts, but there was no Msr1-dependent difference in body weight, glucose metabolism, or insulin resistance. Flow cytometry revealed no significant differences between genotypes in ATM subtypes or proliferation in male and female mice. We observed increased frequency of proliferating ATMs in obese female compared to male mice. Overall, we conclude that while MSR1 is a biomarker of diabetes status in human adipose tissue, in mice Msr1 is not required for obesity-associated insulin resistance or ATM accumulation.

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“…In turn, they can be activated or differentiate into macrophages, initiating the secretion of cytokines and chemokines to exacerbate inflammation ( Lackey and Olefsky, 2016 ; McNelis and Olefsky, 2014 ). Given the role of macrophages in obesity, sex differences in macrophages are of particular interest and have been demonstrated before ( Gal-Oz et al, 2019 ; Varghese et al, 2022 ). Visceral fat contains more infiltrating macrophages and higher expression of inflammatory cytokines than subcutaneous fat ( Weisberg et al, 2003 ; Strissel et al, 2007 ), and male visceral adipose tissues accumulate more macrophages than females ( Chen et al, 2021a ; Chen et al, 2021b ).…”

Section: Introductionmentioning

confidence: 94%

Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils

Ruggiero-Ruff

et al. 2023

eLife

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Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity comorbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high-fat diet (HFD)-induced obesity. Compared to male mice, serum RELMα levels were higher in both control and HFD-fed females and correlated with frequency of adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had proinflammatory macrophage accumulation and eosinophil loss in the adipose stromal vascular fraction (SVF), while RELMα treatment or eosinophil transfer rescued this phenotype. Single-cell RNA-sequencing of the adipose SVF was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283/Gm21887, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα–macrophage–eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.

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Monocyte Trafficking and Polarization Contribute to Sex Differences in Meta-Inflammation

Cited by 16 publications

References 74 publications

Monocyte-derived Dll4 is a novel contributor to persistent systemic inflammation in HIV patients

Monocyte-derived Dll4 is a novel contributor to persistent systemic inflammation in HIV patients

MSR1 is not required for obesity-associated inflammation and insulin resistance in mice

Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils

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