Abstract
Human skin functions as a physical barrier, preventing the entry of foreign pathogens while also accommodating a myriad of commensal microorganisms. A key contributor to the skin landscape is the sebaceous gland. Mice devoid of sebocytes are prone to skin infection, yet our understanding of how sebocytes function in host defense is incomplete. Here, we show that the small proline-rich proteins, SPRR1 and SPRR2 are bactericidal in skin. SPRR1B and SPPR2A were induced in human sebocytes by exposure to the bacterial cell wall component lipopolysaccharide (LPS). Colonization of germ-free mice was insufficient to trigger increased SPRR expression in mouse skin, but LPS injected into mouse skin stimulated increased expression of the mouse SPRR orthologous genes, Sprr1a and Sprr2a, through activation of MYD88. Both mouse and human SPRR proteins displayed potent bactericidal activity against MRSA (methicillin-resistant Staphylococcus aureus), Pseudomonas aeruginosa, and skin commensals. Thus, Sprr1a-/-;Sprr2a-/- mice are more susceptible to MRSA and P. aeruginosa skin infection. Lastly, mechanistic studies demonstrate that SPRR proteins exert their bactericidal activity through binding and disruption of the bacterial membrane. Taken together, these findings provide insight into the regulation and antimicrobial function of SPRR proteins in skin and how the skin defends the host against systemic infection.
Highlights
The skin is the human body’s largest organ, with direct contact with the external environment including bacteria, fungi, viruses and parasites infection results
small proline-rich protein (SPRR) proteins were originally identified in skin as markers of terminal differentiation that function as substrates of transglutaminase in the crosslinked cornified envelope present at the skin surface this study, we demonstrate that SPRR1 and SPRR2 proteins function as antimicrobial proteins in the skin
Defending the host from invasion by pathogens like S. aureus and P. aeruginosa is one of the chief functions of the skin uncharacterized group of antibacterial proteins expressed by keratinocytes and sebaceous gland cells, which can rapidly kill pathogens through membrane disruption and limit bacterial skin infection
Summary
The skin is the human body’s largest organ, with direct contact with the external environment including bacteria, fungi, viruses and parasites infection results. Skin and soft tissue infections pose a considerable public health threat. Adding to the challenges of treating infections posed by these pathogens has been the development of antibiotic resistant strains of bacteria such as methicillin resistant Staphylococcus aureus (MRSA) 8. Skin antimicrobial proteins (AMPs) play an essential role in defending the host from the invasion of pathogens immune effectors that rapidly kill bacteria by targeting bacterial cell wall or cell membrane structures cathelicidins, resistin and S100 proteins, have been identified and characterized in skin. Sebaceous glands (SGs) are specialized epithelial cells that cover the entire skin surface except the palms and soles. SGs excrete a lipid-rich and waxy substance called sebum to the skin surface
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