Diet-induced obesity promotes infection by impairment of the innate antimicrobial defense function of dermal adipocyte progenitors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE150729 | GEO | 2021/05/07
REPOSITORIES: GEO
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Project description:Infections are a major complication of obesity, but the mechanisms responsible for impaired defense against microbes are not well understood. Here, we found that adipocyte progenitors were lost from the dermis during diet-induced obesity (DIO) in humans and mice. The loss of adipogenic fibroblasts from mice resulted in less antimicrobial peptide production and greatly increased susceptibility to Staphylococcus aureus infection. The decrease in adipocyte progenitors in DIO mice was explained by expression of transforming growth factor-β (TGFβ) by mature adipocytes that then inhibited adipocyte progenitors and the production of cathelicidin in vitro. Administration of a TGFβ receptor inhibitor or a peroxisome proliferator-activated receptor-γ agonist reversed this inhibition in both cultured adipocyte progenitors and in mice and subsequently restored the capacity of obese mice to defend against S. aureus skin infection. Together, these results explain how obesity promotes dysfunction of the antimicrobial function of reactive dermal adipogenesis and identifies potential therapeutic targets to manage skin infection associated with obesity.
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Project description:Diet-induced obesity promotes infection by impairment of the innate antimicrobial defense function of dermal adipocyte progenitors
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Project description:Dermal fibroblasts (dFB) resist infection by locally differentiating into adipocytes and producing the antimicrobial peptide cathelicidin in response to S. aureus. We found that neonatal dFB were highly adipogenic whereas this adipogenic function was lost during adulthood. To better understand the molecular nature of the change in antimicrobial and adipogenic function of dFB, we profiled the transcriptomes of primary dFB isolated at different ages by RNA-seq. RNA-seq identified the pro-adipogenic to pro-fibrotic gene signature switch in dFB during aging, and identified TGF-beta as the top up-regulated pathway that was activated in 2M dFB compared to neonatal P1 dFB.
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Project description:This special issue intends to review and update our understanding of the antimicrobial defense mechanisms of the skin and oral cavity. These two environments are quite different in terms of water, pH, and nutrient availability, but have some common antimicrobial factors. The skin surface supports the growth of a limited range of microorganisms but provides a hostile environment for others. The growth of most microorganisms is prevented or limited by the low pH, scarcity of some nutrients such as phosphorus and the presence of antimicrobial peptides, including defensins and cathelicidins, and antimicrobial lipids, including certain fatty acids and long-chain bases. On the other hand, the oral cavity is a warm, moist, nutrient rich environment which supports the growth of diverse microflora. Saliva coating the oral soft and hard surfaces determines which microorganisms can adhere to these surfaces. Some salivary proteins bind to bacteria and prevent their attachment to surfaces. Other salivary peptides, including defensins, cathelicidins, and histatins are antimicrobial. Antimicrobial salivary proteins include lysozyme, lactoferrin, and lactoperoxidase. There are also antimicrobial fatty acids derived from salivary triglycerides and long-chain bases derived from oral epithelial sphingolipids. The various antimicrobial factors determine the microbiomes of the skin surface and the oral cavity. Alterations of these factors can result in colonization by opportunistic pathogens, and this may lead to infection. Neutrophils and lymphocytes in the connective tissue of skin and mucosa also contribute to innate immunity.
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Project description:Epithelial cells express antimicrobial proteins in response to invading pathogens, although little is known regarding epithelial defense mechanisms during healthy conditions. Here we report that epithelial cytokeratins have innate defense properties because they constitutively produce cytoprotective antimicrobial peptides. Glycine-rich C-terminal fragments derived from human cytokeratin 6A were identified in bactericidal lysate fractions of human corneal epithelial cells. Structural analysis revealed that these keratin-derived antimicrobial peptides (KDAMPs) exhibited coil structures with low α-helical content. Synthetic analogs of these KDAMPS showed rapid bactericidal activity against multiple pathogens and protected epithelial cells against bacterial virulence mechanisms, while a scrambled peptide showed no bactericidal activity. However, the bactericidal activity of a specific KDAMP was somewhat reduced by glycine-alanine substitutions. KDAMP activity involved bacterial binding and permeabilization, but the activity was unaffected by peptide charge or physiological salt concentration. Knockdown of cytokeratin 6A markedly reduced the bactericidal activity of epithelial cell lysates in vitro and increased the susceptibility of murine corneas to bacterial adherence in vivo. These data suggest that epithelial cytokeratins function as endogenous antimicrobial peptides in the host defense against infection and that keratin-derived antimicrobials may serve as effective therapeutic agents.
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Project description:The epidermal skin barrier protects the body from a host of daily challenges, providing protection against mechanical insults and the absorption of chemicals and xenobiotics. In addition to the physical barrier, the epidermis also presents an innate defense against microbial overgrowth. This is achieved through the presence of a diverse collection of microorganisms on the skin (the "microbiota") that maintain a delicate balance with the host and play a significant role in overall human health. When the skin is wounded, the local tissue with a compromised barrier can become colonized and ultimately infected if bacterial growth overcomes the host response. Wound infections present an immense burden in healthcare costs and decreased quality of life for patients, and treatment becomes increasingly important because of the negative impact that infection has on slowing the rate of wound healing. In this review, we discuss specific challenges of treating wound infections and the advances in drug delivery platforms and formulations that are under development to improve topical delivery of antimicrobial treatments.
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Project description:Antimicrobial peptides, such as defensins or cathelicidins, are effector substances of the innate immune system and are thought to have antimicrobial properties that contribute to host defense. The evidence that vertebrate antimicrobial peptides contribute to innate immunity in vivo is based on their expression pattern and in vitro activity against microorganisms. The goal of this study was to investigate whether the overexpression of an antimicrobial peptide results in augmented protection against bacterial infection. C57BL/6 mice were given an adenovirus vector containing the cDNA for LL-37/hCAP-18, a human cathelicidin antimicrobial peptide. Mice treated with intratracheal LL-37/hCAP-18 vector had a lower bacterial load and a smaller inflammatory response than did untreated mice following pulmonary challenge with Pseudomonas aeruginosa PAO1. Systemic expression of LL-37/hCAP-18 after intravenous injection of recombinant adenovirus resulted in improved survival rates following intravenous injection of lipopolysaccharide with galactosamine or Escherichia coli CP9. In conclusion, the data demonstrate that expression of an antimicrobial peptide by gene transfer results in augmentation of the innate immune response, providing support for the hypothesis that vertebrate antimicrobial peptides protect against microorganisms in vivo.
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