Hypersensitive IFN Responses in Lupus Keratinocytes Reveal Key Mechanistic Determinants in Cutaneous Lupus

Tsoi, Lam C.; Hile, Grace A.; Berthier, Céline C.; Sarkar, Mrinal K.; Reed, T. Edward; Liu, Jianhua; Uppala, Rattapon; Patrick, Matthew; Raja, Kalpana; Xing, Xianying; Xing, Enze; He, Kevin; Guðjónsson, Jóhann E.; Kahlenberg, J. Michelle

doi:10.4049/jimmunol.1800650

Cited by 51 publications

(34 citation statements)

References 52 publications

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“…Keratinocytes from patients with SLE demonstrate low expression of barrier-related genes and increased adherence to S. aureus Given that IFNs downregulate barrier genes and nonlesional keratinocytes from patients with SLE express elevated type I IFNs (IFN-k) at baseline (Sarkar et al, 2018), we next explored whether barrier genes were differentially expressed in nonlesional SLE and control keratinocytes (HCs). To this end, keratinocytes were obtained from nonlesional skin and subjected to RNA sequencing analysis as reported previously (Tsoi et al, 2019). Barrier genes such as FLG, LOR, IVL, and CLDN1, as well as antimicrobial peptides (DEFB), were repressed in SLE keratinocytes in comparison with HC keratinocytes ( Figure 4).…”

Section: Exposure To Ifns Results In Diminished Barrier Gene Expressionmentioning

confidence: 88%

“…RNA sequencing data was obtained from keratinocytes isolated from nonlesional control and systemic lupus erythematosus skin as previously reported (RNA sequencing data is available in Gene Expression Omnibus; accession number GSE124939) (Tsoi et al, 2019). RNA sequencing log 2 expression values were averaged for each selected gene in each condition.…”

Section: Rna Sequencing Data Analysis and Gene Expression Heatmapmentioning

confidence: 99%

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Staphylococcus aureus Colonization Is Increased on Lupus Skin Lesions and Is Promoted by IFN-Mediated Barrier Disruption

Sirobhushanam

Parsa

Reed

et al. 2020

Journal of Investigative Dermatology

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Cutaneous inflammation is recurrent in systemic lupus erythematosus (SLE), yet mechanisms that drive cutaneous inflammation in SLE are not well defined. Type I IFNs are elevated in nonlesional SLE skin and promote inflammatory responses. Staphylococcus aureus, known to induce IFN production, could play a role in cutaneous inflammation in SLE. We show here that active cutaneous lupus erythematosus lesions are highly colonized (w50%) by S. aureus. To define the impact of IFNs on S. aureus colonization, we examined the effects of type I and type II IFNs on S. aureus adherence and invasion. An increase in adherent S. aureus was observed after exposure to both IFN-a and-g, whereas IFN-g appeared to inhibit invasion of S. aureus. Cutaneous lupus erythematosus lesional skin microarray data and RNA sequencing data from SLE keratinocytes identified repression of barrier gene expression, such as filaggrin and loricrin, and SLE keratinocytes exhibited increased S. aureusebinding integrins. These SLE-associated changes could be replicated by IFN treatment of keratinocytes. Further, SLE keratinocytes exhibited increased binding to S. aureus. 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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Section: Exposure To Ifns Results In Diminished Barrier Gene Expressionmentioning

confidence: 88%

Section: Rna Sequencing Data Analysis and Gene Expression Heatmapmentioning

confidence: 99%

Staphylococcus aureus Colonization Is Increased on Lupus Skin Lesions and Is Promoted by IFN-Mediated Barrier Disruption

Sirobhushanam

Parsa

Reed

et al. 2020

Journal of Investigative Dermatology

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“…Given these data, we next hypothesized that structural cells in the skin may be key responders to IFN-λ and coordinate immune responses through expression of proinflammatory chemokines. Keratinocytes are the most abundant cell type in the skin and have been implicated in the pathogenesis of SLE and other inflammatory skin diseases (36,37). Previous reports have indicated that keratinocytes express the IFNLR and respond to stimulation with IFN-λ cytokine (11,22,38).…”

Section: Ifn-λ Promotes Skin Inflammation and Induces Chemokine Exprementioning

confidence: 99%

“…Further investigation revealed that Ifnlr1 −/− mice had lower expression of proinflammatory cytokines and chemokines (IL6, CXCL9, CXCL10) in skin tissue. Keratinocytes are the most abundant cell type in skin and have been implicated in SLE and a variety of other inflammatory skin diseases (36,37). Previous reports suggest that keratinocytes respond to IFN-λ in vitro (11,38).…”

Section: Ifn-λ Promotes Lupus-associated Renal Pathology and Activatesmentioning

confidence: 99%

Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus

Goel

Wang

O’Neil

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

101

102

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Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1) deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys without effects on autoantibody production. Single-cell RNA sequencing in mouse spleen and human peripheral blood revealed that only mouse neutrophils and human B cells are directly responsive to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and promote tissue inflammation. These data provide insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.

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“…Keratinocytes from CLE patients exhibit an enhanced response to both type-1 and type-2 IFNs ( 156 ), and produce IFNκ ( 157 ), IL-6 ( 158 ), and Type-III IFN (IFNλ) following UVB damage. Cytokine dysregulation in UVB treated CLE keratinocytes provides a link between UV initiation factors and immunopathogenesis ( 156 ). UV treatment of keratinocytes induces upregulation of IFNκ, which plays a key homeostatic role in maintaining IFN balance in skin ( 158 ).…”

Section: Cle Immunopathogenesismentioning

confidence: 99%

Current Insights in Cutaneous Lupus Erythematosus Immunopathogenesis

et al. 2020

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Cutaneous Lupus Erythematosus (CLE) is a clinically diverse group of autoimmune skin diseases with shared histological features of interface dermatitis and autoantibodies deposited at the dermal-epidermal junction. Various genetic and environmental triggers of CLE promote infiltration of T cells, B cells, neutrophils, antigen presenting cells, and NK cells into lesional skin. In this mini-review, we will discuss the clinical features of CLE, insights into CLE immunopathogenesis, and novel treatment approaches.

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Hypersensitive IFN Responses in Lupus Keratinocytes Reveal Key Mechanistic Determinants in Cutaneous Lupus

Abstract: The sequences presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE124939) under accession number GSE124939.

Cited by 51 publications

References 52 publications

Staphylococcus aureus Colonization Is Increased on Lupus Skin Lesions and Is Promoted by IFN-Mediated Barrier Disruption

Staphylococcus aureus Colonization Is Increased on Lupus Skin Lesions and Is Promoted by IFN-Mediated Barrier Disruption

Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus

Current Insights in Cutaneous Lupus Erythematosus Immunopathogenesis

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