Age-Related Loss of Innate Immune Antimicrobial Function of Dermal Fat Is Mediated by Transforming Growth Factor Beta

Immunity. 2019 Jan 15;50(1):121-136.e5. doi: 10.1016/j.immuni.2018.11.003. Epub 2018 Dec 26.

Abstract

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.

Keywords: Staphylococcus aureus; adipocyte progenitors; adipocytes; antimicrobial peptides; cathelicidin; dermal fibroblasts; dermal white adipose tissue; infection; innate immunity; transforming growth factor beta.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipocytes / metabolism
  • Adipogenesis
  • Aging / immunology*
  • Animals
  • Anti-Infective Agents / metabolism
  • Antimicrobial Cationic Peptides / metabolism
  • Cells, Cultured
  • Embryo, Mammalian
  • Fibroblasts / physiology*
  • Humans
  • Immunity, Innate
  • Mice
  • Skin / metabolism*
  • Staphylococcal Infections / immunology*
  • Staphylococcus aureus / physiology*
  • Subcutaneous Fat / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Transforming Growth Factor beta
  • ropocamptide