Age-related loss of innate immune antimicrobial function of dermal fat is mediated by TGFβ
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA497383 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8074760_1.fastq.gz | Fastqsanger.gz | |||
| SRR8074760_2.fastq.gz | Fastqsanger.gz | |||
| SRR8074770_1.fastq.gz | Fastqsanger.gz | |||
| SRR8074770_2.fastq.gz | Fastqsanger.gz | |||
| SRR8074761_1.fastq.gz | Fastqsanger.gz |
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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:Treatment with the toll-like receptor (TLR) 4 agonist monophosphoryl lipid A (MPLA) conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid (TCA) reprogramming to innate immune memory. We observed that MPLA potently induced expression of immunoresponsive gene 1 (Irg1) and accumulation of its byproduct, the TCA cycle metabolite itaconate, in macrophages. Treatment with MPLA enhanced microbial clearance in wild type (WT), but not Irg1-deficient, mice, demonstrating that itaconate contributes to the antimicrobial phenotype in vivo. Treatment with MPLA equally augmented innate leukocyte recruitment, phagocytosis, respiratory burst and cytokine responses in WT and Irg1-deficient innate leukocytes after infection. However, the ability of Irg1-deficient macrophages to kill Pseudomonas aeruginosa was impaired. We further observed that itaconate is directly antimicrobial against P. aeruginosa at pH 5, which is characteristic of the phagolysosome, and is facilitated by reactive oxygen species. RNA sequencing revealed suppressed transcription of genes associated with phagolysosome function in Irg1 deficient macrophages. This study identifies a contribution of itaconate to MPLA-induced augmentation of innate antimicrobial immunity via facilitation of microbial killing.
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Project description:Dermal fibroblasts (dFBs) resist infection by locally differentiating into adipocytes and producing cathelicidin antimicrobial peptide in response to Staphylococcus aureus (S. aureus). Here, we show that neonatal skin was enriched with adipogenic dFBs and immature dermal fat that highly expressed cathelicidin. The pool of adipogenic and antimicrobial dFBs declined after birth, leading to an age-dependent loss of dermal fat and a decrease in adipogenesis and cathelidicin production in response to infection. Transforming growth factor beta (TGF-β), which acted on uncommitted embryonic and adult dFBs and inhibited their adipogenic and antimicrobial function, was identified as a key upstream regulator of this process. Furthermore, inhibition of the TGF-β receptor restored the adipogenic and antimicrobial function of dFBs in culture and increased resistance of adult mice to S. aureus infection. These results provide insight into changes that occur in the skin innate immune system between the perinatal and adult periods of life.
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