1325 Age-dependent loss of the stemness and antimicrobial defense function of dermal fibroblasts is mediated by TGFbeta

Aging is associated with a loss of dermal white adipose tissue (dWAT) and an increased risk of skin and soft tissue infections. Local expansion of dWAT in response to injury or infection (reactive adipogenesis) protects against invasive bacterial infection through the expression of antimicrobial peptides (AMPs). In this study we examined how this defense function is regulated during development and aging and how dysfunction of dWAT may contribute to age-related loss of skin defense. Using a mouse model of S. aureus (SA) skin infection, we found that SA triggered robust reactive adipogenesis and AMP response in young mice, but this response was lost during aging. Cre-LoxP targeted deletion of the AMP gene Camp in Pdgfra+ fibroblasts or Adipoq+ adipocytes led to increased susceptibility of young mice to SA skin infection. Transcriptional analysis of dWAT and primary dermal fibroblasts (dFBs) from human and mouse skin of various ages identified TGFbeta as a top pathway associated with the age-dependent loss of AMP function and the adipogenic to profibrotic shift in dFB function. To validate the role of TGFbeta, adipogenic dFBs were treated with TGFβ2 and this led to a rapid loss of the adipogenic-antimicrobial function. Similarly, iInhibition of TGFBR restored the antimicrobial function of aged dFBs, suppressed their profibrotic features and lead to increased resistance of aged mice to SA infection. Together, these results identify TGFbeta as a central pathway that drives the age-dependent loss of the stemness and antimicrobial function of dFBs, and suggests that small molecules that suppress TGFBR might be effective therapeutics to combat the aging-associated decline in dermal function.