RELMα provides sex-specific protection from obesity through macrophages and eosinophils
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ABSTRACT:
PROVIDER: PRJNA907056 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22474168_1.fastq.gz | Fastqsanger.gz | |||
| SRR22474168_2.fastq.gz | Fastqsanger.gz | |||
| SRR22474169_1.fastq.gz | Fastqsanger.gz | |||
| SRR22474169_2.fastq.gz | Fastqsanger.gz | |||
| SRR22474170_1.fastq.gz | Fastqsanger.gz |
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Project description:The 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 comorbidities with exacerbated inflammation, and females are protected. The focus of this study was to identify sex-specific immune effectors that regulate obesity pathogenesis, focusing on the M2 macrophage signature gene, Resistin-like molecule α (RELMα). Here we performed single cell RNA-sequencing (scRNA-seq) on visceral adipose tissue stromal vascular fraction on wildtype and RELMα knock-out animals, both males and females, on high fat diet. We utilized the 10x Genomics 3’ CellPlex platform, to label cells with cell multiplexing oligos (CMOs) per sample in each group prior to pooling for downstream barcoding and library construction. This study revealed sex-specific and RELMα-dependent cellular targets and population differences of female and RELMα-mediated protection.
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Project description:The skin is the human body’s largest organ and is in contact with a diverse community of microorganisms that includes both resident and pathogenic bacteria. Skin immune defenses include the production of antimicrobial proteins that kill bacteria directly. However, we still have an incomplete understanding of how skin antimicrobial proteins promote homeostasis with resident bacterial communities and limit infection. Here, we show that resistin-like molecule α (RELMα) is an antibacterial protein that is produced by keratinocytes and sebocytes in the mouse skin. RELMα expression was induced in mouse skin by resident and pathogenic skin bacteria and was bactericidal for several bacterial species found on the skin, including Streptococcus pyogenes. Mice lacking RELMα had altered resident skin bacterial communities and were more susceptible to bacterial infection, indicating that RELMα controls bacterial colonization of the skin. RELMα expression required dietary vitamin A and could be induced by therapeutic retinoids that protected against bacterial infection in a RELMα-dependent manner. Resistin, another member of the RELM family, was expressed in human skin, required retinoids for expression, and killed skin bacteria, indicating a conserved function for RELM proteins in skin innate immunity. Our findings thus identify members of the RELM family as antibacterial proteins that provide vitamin A-dependent antimicrobial protection of the skin, and provide insight into why skin immunity requires adequate dietary vitamin A.
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Project description: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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Project description: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 co-morbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high fat diet-induced obesity. Compared to male mice, RELMα levels were elevated in both control and high fat dietfed females and correlated with adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had pro-inflammatory macrophage accumulation and eosinophil loss, while both RELMα treatment and eosinophil transfer rescued this phenotype. Single cell RNA-sequencing of the adipose stromal vascular fraction was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283, 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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