Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin dryness, inflammation, and itch. A major hallmark of AD is an elevation of the immune cytokines IL-4 and IL-13. These cytokines lead to skin barrier disruption and lipid abnormalities in AD, yet the underlying mechanisms are unclear. Sebaceous glands are specialized sebum-producing epithelial cells that promote skin barrier function by releasing lipids and antimicrobial proteins to the skin surface. Here, we show that in AD, IL-4 and IL-13 stimulate the expression of 3β-hydroxysteroid dehydrogenase 1 (HSD3B1), a key rate-limiting enzyme in sex steroid hormone synthesis, predominantly expressed by sebaceous glands in human skin. HSD3B1 enhances androgen production in sebocytes, and IL-4 and IL-13 drive lipid abnormalities in human sebocytes and keratinocytes through HSD3B1. Consistent with our findings in cells, HSD3B1 expression is elevated in the skin of AD patients and can be restored by treatment with the IL-4Rα monoclonal antibody, Dupilumab. Androgens are also elevated in a mouse model of AD, though the mechanism in mice remains unclear. Our findings illuminate a connection between type 2 immunity and sex steroid hormone synthesis in the skin and suggest that abnormalities in sex steroid hormone synthesis may underlie the disrupted skin barrier in AD. Furthermore, targeting sex steroid hormone synthesis pathways may be a therapeutic avenue to restoring normal skin barrier function in AD patients.

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 triggered the expression of the mouse SPRR orthologous genes, Sprr1a and Sprr2a, through stimulation 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 Pseudomonas 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 d Host responses produce distinct Ebola virus outcomes in genetically diverse mice d Tolerant outcomes result from early inflammatory responses and sustained regulation d Lethality is linked to early gene suppression and uncontrolled inflammation d Murine transcriptional profiles can be used to predict clinical outcome in humans

Human skin prevents the entry of foreign pathogens while also accommodating a myriad of commensal microorganisms. A key contributor to skin immunity is the sebaceous gland, yet our understanding of how sebocytes function in host defense is incomplete. Here we show that sebaceous glands respond to bacterial stimuli by generating small proline-rich-proteins, SPRR1B and SPRR2A, which display bactericidal functions in skin. Further, LPS injected into mouse skin triggers the expression of the mouse SPRR orthologous genes, Sprr1a and Sprr2a. Both mouse and human SPRR-proteins display potent bactericidal activity against methicillinresistant Staphylococcus aureus and Pseudomonas aeruginosa. Thus, Sprr1a;Sprr2a −/− mice are more susceptible to skin infection with these bacteria. Lastly, our findings demonstrate that SPRR proteins exert their bactericidal activity through binding and disruption of the bacterial membrane. These findings provide insight into the regulation of SPRR proteins in skin and how the sebaceous gland contributes to host defense.

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