Despite improvements in connection technology and prophylactic measures, peritonitis remains a major complication of peritoneal dialysis (PD), causing technique failure and increased morbidity and mortality (1). Because it is a common cause of skin infection, Staphylococcus aureus (S. aureus) is one of the most frequent etiological agents of catheter-related peritonitis in PD patients. Moreover, the frequency of methicillin-resistant S. aureus (MRSA) is increasing, associated with lower primary response rates and worse outcomes (2). Reducing the frequency and severity of peritonitis in patients treated by PD and understanding the basis of virulence and infection control remain high priorities and major challenges for researchers.
In a recent study published in Science, R. Gallo and colleagues describe elegant experiments demonstrating, for the first time, that skin adipocytes are involved in the protection against S. aureus infections (3). Using a mouse model of subcutaneous injection of MRSA in the dermis, these investigators noted that the pathogens caused a marked expansion of the dermal fat layer caused by the hypertrophy and proliferation of adipocytes. The adipogenesis due to S. aureus infection was driven by specific transcription factors (called zinc finger protein 423, ZFP423; and peroxisome proliferator-activated receptor γ, PPAR-γ). Next, they showed that adipocyte activation was important for host defense against S. aureus, by using mouse models defective in ZPF423 or by treating normal mice with pharmacological inhibitors of PPAR-γ. In both cases, impaired adipogenesis resulted in increased susceptibility to S. aureus skin infection.
In order to find out how adipocytes might protect against S. aureus infection, the authors compared the expression of antimicrobial peptide genes in a well-established model of undifferentiated vs mature, differentiated mouse (3T3-L1) adipocytes. They discovered that the mouse antimicrobial peptide cathelicidin was strongly and specifically induced during differentiation of the adipocytes. Cathelicidin was also produced by human adipocytes and detected in human and mouse subcutaneous adipose tissue, and its production by adipocytes was significantly enhanced during S. aureus infection in vitro and in vivo. Furthermore, conditioned medium containing secreted cathelicidin inhibited the growth of S. aureus, whereas mice knocked out for the Camp gene, which codes for cathelicidin, were more susceptible to infection. Also, adipocytes from the Camp KO mice lost the capacity to inhibit bacterial growth.
Taken together, these findings show that adipocytes produce an antimicrobial peptide which is important for protection against S. aureus infection. Adipocytes are thus joining other resident cell types and recruited leukocytes in the host defense against microbial infections. If verified for other types of adipocytes, including those located in the visceral peritoneum, the role of adipocytes in innate immunity could open a new avenue into the control of invading pathogens and of the infectious complications in PD.
REFERENCES
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