Background/Purpose: Background/Purpose: Cutaneous inflammation is recurrent in systemic lupus erythematosus (SLE) and is often triggered by exposure to ultraviolet B (UVB) light. Type I interferons (IFN) play a critical role in SLE skin inflammation and are increased in non-lesional SLE keratinocytes. Mechanisms that drive cutaneous inflammation in SLE are not well-defined and may involve microbial dysbiosis, an underexplored source of cutaneous IFNs. Staphylococcus aureus, known to induce IFN production, could play a role in cutaneous inflammation in SLE. This study thus evaluated the colonization of lupus skin by S. aureus and the extent to which IFNs drive increased colonization rates by S. aureus.

Methods: Methods: Patients with SLE who fulfilled >4 ACR criteria for diagnosis were recruited from the Michigan Lupus Cohort. Nares, chest, and lupus related skin lesions were swabbed and analyzed for S. aureus colonization. To define the impact of IFNs on S. aureus colonization, we examined the effect of type I and type II IFNs (1000U/ml) on barrier gene expression in N/TERTs (a keratinocyte cell line) by real time quantitative PCR (RT-qPCR). Adhesion and invasion of log-phase S. aureus was assessed using confluent N/TERTs treated with IFNα or IFNγ. Adhered S. aureus were quantified by counting colony forming units (CFUs). Cells were treated with gentamicin (200 μg/ml) for invasion assays prior to CFU quantification. Keratinocytes were exposed to baricitinib (10 μg/ml) prior to IFN exposure to block IFN signaling. Primary keratinocytes were isolated from non-lesional skin of SLE patients and matched healthy adults and utilized for RNA-seq analysis as well as adhesion and invasion assays.

Results: Results: We show here that active lupus lesions are highly colonized (~50%) by S. aureus. Microarray data from SLE lesional skin revealed lower expression of various cutaneous barrier genes such as filaggrin (FLG). IFN-exposed keratinocytes demonstrated lower expression of barrier related genes such as FLG, loricrin and involucrin. This repression of barrier genes was also seen in primary SLE keratinocytes without additional IFN treatment via RNA-seq. We next examined the role of IFN exposure on S. aureus colonization by adhesion and invasion assays. S. aureus adherence was significantly higher in keratinocytes that were exposed to IFNα but not IFNγ. RT-qPCR analysis showed higher expression of α-integrin in IFNα but not IFNγ exposed keratinocytes, indicating a possible mechanism for higher S. aureus adherence. In addition, IFNγ exposure appeared to inhibit invasion of S. aureus into keratinocytes. Confirming a role for IFNs in primary cells, S. aureus adhered better to SLE keratinocytes than healthy control keratinocytes. Exposure to baricitinib reduced IFNα-promoted S. aureus adherence, thus confirming specificity of the IFN activity.

Conclusion: Conclusion: SLE lesional skin is highly colonized by S. aureus and exhibits lower barrier gene expression indicating barrier compromise. IFN exposure inhibits barrier gene expression and IFNα promotes S. aureus adhesion. Together, these data suggest that chronic exposure to IFNs induces barrier disruption that allows for higher S. aureus colonization in SLE skin.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/staphylococcus-aureus-colonization-is-increased-on-lupus-skin-lesions-and-is-promoted-by-interferon-mediated-barrier-disruption/