Staphylococcus aureus skin colonization promotes lupus-like autoimmune inflammation

 HITOSHI TERUI HTTPS://ORCID.ORG/0000-0002-7598-2833KENSHI YAMASAKI HTTPS://ORCID.ORG/0000-0002-5495-4956 MOYUKA WADA-IRIMADA HTTPS://ORCID.ORG/0000-0003-3908-4339MAYUKO ONODERA-AMAGAI HTTPS://ORCID.ORG/0000-0002-8243-8537NAOKAZU HATCHOME HTTPS://ORCID.ORG/0000-0001-8551-2184MASATO MIZUASHI HTTPS://ORCID.ORG/0000-0003-0977-4443RIU YAMASHITATAKESHI KAWABE HTTPS://ORCID.ORG/0000-0001-7173-4472NAOTO ISHII HTTPS://ORCID.ORG/0000-0002-0549-8245[...]SETSUYA AIBA 

DOI: 10.1126/sciimmunol.abm9811

Skin staph promotes lupus

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects various organs, and the microbiota of the nasal cavity and gut are involved in SLE development. However, it is unclear how the skin microbiota influences SLE. Using an epithelial cell–specific IκBζ-deficient (NfkbizΔK5) mouse model of spontaneous skin inflammation, Terui et al. tested the impact of Staphylococcus aureus colonization of the skin on SLE-associated effects. The authors found that the spontaneous SLE-associated effects seen in the NfkbizΔK5 mice worsened with skin S. aureus colonization. These effects were associated with neutrophil extracellular trap (NET)–induced epidermal apoptosis via the increased production of IL-17A. Thus, skin S. aureus colonization potentially worsens SLE by mediating increased release of NETs.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation of various organs such as skin, kidneys, bones, and brain and the presence of autoantibodies. Although the cause of SLE is not completely understood, environmental factors, genetic susceptibility, hormone factors, and environmental factors are thought to play essential roles in the pathogenesis of SLE. Among environmental factors, the microbiota are linked to the development of different autoimmune diseases. The microbiota in the nasal cavity and gut are involved in SLE development, but the influence of skin microbiota is still unclear. Here, we demonstrated that epithelial cell–specific IκBζ-deficient (NfkbizΔK5) mice showed spontaneous skin inflammation with increased abundance of Staphylococcus aureus on the skin. When S. aureus was epicutaneously applied on NfkbizΔK5 mice, NfkbizΔK5 mice developed SLE-associated autoantibodies, anti-dsDNA antibodies, anti-Sm antibodies, and glomerulonephritis with IgG deposition. Epicutaneous S. aureus application significantly increased staphylococcal colonization on the skin of NfkbizΔK5 mice with reduced expression of several antimicrobial peptides in the skin. This staphylococcal skin colonization promoted caspase-mediated keratinocyte apoptosis and neutrophil activation, inducing the interleukin-23 (IL-23)/IL-17 immune response by activating dendritic cells and T cells. Furthermore, the subcutaneous administration of anti–IL-23p19 and anti–IL-17A antibodies alleviated the systemic autoimmune response. Together, these findings underscore epithelial-immune cross-talk disturbances caused by skin dysbiosis as an essential mediator inducing autoimmune diseases.

https://www.science.org/doi/10.1126/sciimmunol.abm9811