NEW YORK (Reuters Health) – Transforming growth factor beta (TGF-beta) is a key regulator of fat and immunity loss in dermal fibroblasts, and interventions targeting this pathway might effectively fight skin infections, researchers say.
Dermal fibroblasts resist infection by differentiating into adipocytes and producing cathelidicin, an antimicrobial peptide, in response to Staphylococcus aureus and other pathogens, according to Dr. Richard Gallo of the University of California, San Diego, and colleagues.
The team studied changes in the adipogenic function of these fibroblasts during embryonic and adult development in mouse and human skin.
As reported online December 26 in Immunity, they found that while neonatal skin is enriched with adipogenic dermal fibroblasts as well as immature dermal fat that highly expresses cathelidicin, the pool of such cells decreases with age; this leads to a loss of dermal fat and a decrease in adipogenesis and cathelidicin production in response to infection.
Further, TGF-beta was identified as a key upstream regulator of this process.
Additional experiments showed that TGF-beta receptor inhibition restored the adipogenic and antimicrobial functions of dermal fibroblasts in culture, and increased the resistance of adult mice to S. aureus infection. Therefore, the researchers suggest, “small molecules that suppress (the TGF-beta receptor) might be an effective therapeutic to combat skin infections.”
Dr. Gallo told Reuters Health, “Our next research steps are to further understand how the control of dermal fat relates to diseases associated with obesity and fibrosis. In particular, we believe that the increase in skin infections that complicate diabetes is related to this biologic system.”
“We hope to design interventions that could improve the immune defense provided by dermal fat, and thus better defend against infections,” he said by email. “We know many groups are interested in the clinical problems related to this newly discovered process, and I am hopeful that the combined efforts, and great support from the NIH, will lead to patient care advances in the next two to five years.”
Dr. Michael Sporn, Active Professor Emeritus/Pharmacology/Molecular and Systems Biology at Dartmouth Medical School in Hanover, New Hampshire, commented, “The authors are to be congratulated on the extensive new findings that they have made. The big question is, ‘What do these experiments mean for human health?'”
“The pronounced effects of TGF-beta on fibroblast phenotype and function have been known for more than 30 years,” he said by email. Although numerous agents have been developed to modulate this process, he added, there still isn’t effective widespread use of agents that regulate TGF-beta signaling.
“One reason for this is the contextual nature of TGF-beta signaling: in one context TGF-beta may exert a specific action, and in another context, it may do just the opposite,” he told Reuters Health. “I would be particularly concerned about the clinical use of anti-TGF-beta in diabetic patients, since TGF-beta can even regulate pancreatic islet cell function.”
“Another problem is the extent to which findings in mouse skin can be extrapolated to humans,” he added.
“Given the total amount of effort currently being made, worldwide, to develop specific agents to regulate TGF-beta signaling and to use such agents for clinical benefit, there may yet be practical applications of the authors’ new findings,” he acknowledged. “But a great deal more work needs to be done before this happens in patients.”
Dr. Nikolaos Frangogiannis, Professor of Microbiology and Immunology and the Edmond J Safra Chair in Cardiovascular Medicine at Albert Einstein College of Medicine in New York City, said by email, “Overall, the evidence is robust and supports the conclusions.”
However, he expressed a number of concerns. “TGF-betas modulate phenotype and function in practically all cell types,” he told Reuters Health. For example, in the skin alone, they can modulate keratinocytes, adipocytes, fibroblasts, vascular cells and immune cells.
“Although there is no doubt…that fibroblasts are major players in antimicrobial protection, modulation of all other cell types by TGF-betas is likely to play an important role in regulation of cutaneous homeostasis and in immune and reparative responses,” he said.
“Thus, the notion that TGF-beta acts as an inhibitor of antimicrobial protection, on the basis of data examining actions exclusively on fibroblasts, paints an oversimplified picture,” he told Reuters Health. “This is not a criticism of the study,” he said. Rather, it highlights “the complexity of the cell biology involved.”
Like Dr. Sporn, Dr. Frangogiannis noted that TGF-betas target all cell types, not just fibroblasts. “Even if restricted to the skin, TGF-beta receptor inhibition could have adverse consequences that may outweigh any antimicrobial benefits mediated through fibroblast modulation.”
“Experiments testing TGF-beta receptor inhibitors in vivo are feasible and would be critical to further develop this direction,” he concluded.