Adipocyte-derived CRAMP–neutrophil serine protease interaction axis regulates innate cutaneous defense against Staphylococcus aureus

Dermal adipocytes have emerged as active participants in cutaneous host defense. In parallel, adipocyte hypertrophy and hyperplasia–driven obesity has become a global public health priority and is strongly associated with increased risk and severity of bacterial infections. Here, we established and optimized two complementary S. aureus infection models—epidermal and subcutaneous—and in combination with diet-induced (HFD) and genetic ( ob/ob ) obesity, to systematically evaluate cathelin-related antimicrobial peptide (CRAMP) expression in adipocytes and its crosstalk with neutrophils. Obese mice displayed impaired cutaneous defense despite marked thickening of the fat layer, characterized by attenuated induction of adipocyte CRAMP and reduced local antibacterial activity. In vitro, CRAMP followed a biphasic pattern during adipocyte differentiation—upregulated at early stages but diminished with advanced maturation and lipid accumulation. Mechanistically, neutrophils processed adipocyte-derived CRAMP via serine proteases to generate shorter peptides with enhanced antibacterial activity. Collectively, these findings identify a CRAMP–neutrophil (serine protease) interaction axis as a key amplifier of cutaneous innate immunity and provide mechanistic insight into obesity-associated susceptibility to skin infection, suggesting potential avenues for targeted intervention.