Scientists in the U.S. and China have shown how dermal fibroblasts (dFBs) found deep in the skin layer convert into fat cells that not only give skin its youthful, plump appearance, but also fight bacterial infections by producing an antimicrobial peptide called cathelicidin in response to invading Staphylococcus aureus pathogens. The mouse and human tissue studies, headed by Richard L. Gallo, M.D., Ph.D., distinguished professor and chair of the department of dermatology at the University of California, San Diego (UCSD) School of Medicine, also found that this pool of adipogenic dFBs and immature dermal fat cells declines after birth, in line with TGF-β pathway activation, which results in reduced production of cathelicidin, and so compromised ability to stave off S. aureus infections.
“We have discovered how the skin loses the ability to form fat during aging,” Dr. Gallo said. “Loss of the ability of fibroblasts to convert into fat affects how the skin fights infections and will influence how the skin looks during aging.” Reporting their findings in a paper in Immunity, the researchers concluded, “This work provides insights into how activation of TGF-β negatively affects skin defense against infection and suggests that small molecules that suppress TGFBR might be an effective therapeutic to combat skin infections.” Their report is titled, “Age-Related Loss of Innate Immune Antimicrobial Function of Dermal Fat is Mediated by Transforming Growth Factor Beta.”
Skin provides a physical and immunological barrier that protects internal tissues. Dermal fibroblasts generate connective tissue and help the skin to recover following injury, but some can differentiate into fat cells. The resulting dermal white adipose tissue (dWAT) is the deepest barrier of the skin, and was, until recently, thought to serve as an energy reservoir and insulating layer, the authors wrote. However, more recent research indicates that dWAT also plays a role in processes including hair follicle regeneration, wound healing, thermogenesis, and protection against skin infections, the authors wrote.
S. aureus is the primary cause of skin and soft tissue infections in humans, and methicillin-resistant S. aureus (MRSA) infections have, over the last two decades, been responsible for more deaths in the U.S. than any other pathogen, they continued. “… a better understanding of skin host defense mechanisms against S. aureus is acutely needed for developing strategies to combat the important public health problem.”
S. aureus infection triggers the rapid differentiation of dermal fibroblast-derived preadipocytes (pAds) into immature adipocytes (Ads), a process called reactive adipogenesis. The antimicrobial peptide cathelicidin (Camp) is expressed during this differentiation process. “This expression of Camp is necessary to limit bacterial spread because the inhibition of this adipogenic-antimicrobial function of immature ADs leads to increased susceptibility to S. aureus infection,” the researchers explained. To investigate the regulation of reactive adipogenesis in skin immunity, the team looked at changes in adipogenic function of dFBs at different ages in mouse and human skin.
Initial findings showed that mice engineered to lack Camp in dermal adipocytes were more susceptible to S. aureus infection than wild-type controls. Studies in mice also showed an age-related decline in the reactive adipogenesis in response to S. aureus infection, which was linked with evidence of reduced cathelicidin production. Further analyses linked aging with a progressive loss of adipogenic dFBs and immature dermal fat, and a reduction in adipogenic antimicrobial function.
RNA sequencing of mouse dFBs isolated at different ages suggested that this loss of antimicrobial and adipogenic functions in older dFBs was linked with TGF-β pathway activation, “indicating that TGF-β could play a role in the age-related switch from pro-adipogenic to pro-fibrotic dFBs,” the authors write.
Interestingly, treating neonatal dFBs using recombinant mouse TGF-β2 effectively suppressed the adipogenic function of these otherwise youthful dFBs, and also reduced cathelicidin expression. The antimicrobial activity of differentiating neonatal dFBs against S. aureus was also suppressed after the addition of TGF-β2. “These results demonstrate that TGF-β2 is a potent suppressor of dFBs’ capacity to differentiate into ADs and provide antimicrobial activity,” the researchers noted.
The team next confirmed that TGF-β levels and signaling increased in the dermis of mice with increasing age, and demonstrated that chemically inhibiting the TGF-β pathway in the skin of mature mice allowed older dFBs to convert into fat cells, generate a more expansive dWAT layer, and express cathelicidin. Chemically inhibiting TGF-β pathway in adult mice also improved the animals’ ability to fight off S. aureus skin infections. “Infection triggered reactive adipogenesis responses, including enhanced adipocyte hyperplasia and cathelicidin protein production …” the authors noted.
When the team analyzed dWAT in human skin samples from neonates and adults of varying ages, they found that neonatal skin contained a large volume of dWAT, while dWAT decreased in parallel with increasing age. “Babies have a lot of this type of fat under the skin, making their skin inherently good at fighting some types of infections,” Dr. Gallo commented. “Aged dermal fibroblasts lose this ability and the capacity to form fat under the skin. “Skin with a layer of fat under it looks more youthful. When we age, the appearance of the skin has a lot to do with the loss of fat.”
Expression of Camp RNA was also much higher in neonatal skin than in older skin samples, and staining for cathelicidin showed that while the peptide was abundantly expressed in neonatal dermal ADs it wasn’t as abundant in aged skin. Analyses indicated that, just as had been observed in mice, TGF-β was also critical to the loss of adipogenic-antimicrobial function of human dFBs.
“In conclusion, these observations have uncovered that an age-dependent activation of the TGF-β pathway attenuates adipogenic function of dermal fibroblasts and promotes a subsequent loss of antimicrobial defense by dermal fat,” the authors concluded. “These results provide insight into changes that occur in the skin innate immune system between the perinatal and adult periods of life.”