Nonlesional lupus skin contributes to inflammatory education of myeloid cells and primes for cutaneous inflammation

Billi, Allison C.; Ma, Feiyang; Plazyo, Olesya; Gharaee−Kermani, Mehrnaz; Wasikowski, Rachael; Hile, Grace A.; Xing, Xianying; Yee, Christopher; Rizvi, Syed Monem; Maz, Mitra P.; Berthier, Céline C.; Wen, Fei; Tsoi, Lam C.; Pellegrini, Matteo; Modlin, Robert L.; Gudjonsson, Johann E.; Kahlenberg, J. Michelle

doi:10.1126/scitranslmed.abn2263

Cited by 79 publications

(61 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given the known role of heterogeneous fibroblast subsets in both activating and suppressing the local immune response, understanding whether and how upper-dermal fibroblasts are functionally contributing to or restraining disease may provide insights into mechanisms underlying PsO and related skin inflammatory conditions (53). Examination of distal uninvolved skin similarly revealed high interferon signatures in patients with cutaneous lupus (54). Whether other organs or tissues beyond the skin are also affected by inflammatory skin disease while maintaining their normal function, or whether signatures of skin inflammation are uniquely observed in distal skin, remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems

et al. 2023

Self Cite

View full text Add to dashboard Cite

Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.

show abstract

Section: Discussionmentioning

confidence: 99%

Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…2B). Please note that we did not use uninvolved psoriatic skin as control, since it had recently been shown in lupus erythematosus that macroscopically uninvolved skin may be in a preactivated inflammatory stage [20]. All other cell types did not show different percentages of positive cells (data not shown).…”

Section: Mapping Of Cytokines On Cellular Subtypesmentioning

confidence: 94%

Single‐cell transcriptomics reveals prominent expression of IL‐14, IL‐18, and IL‐32 in psoriasis

Frost,

Schmidt,

Klein

et al. 2023

Eur J Immunol

View full text Add to dashboard Cite

RationalePsoriasis is a chronic inflammatory skin disease involving different cytokines and chemokines.ObjectivesHere we use single‐cell transcriptomic analyses to identify relevant immune cell and non‐immune cell populations for an in‐depth characterization of cell types and inflammatory mediators in this disease.MethodsPsoriasis skin lesions of 8 patients are analyzed using single‐cell technology. Data are further validated by in situ hybridization (ISH) of human tissues, serum analyses of human samples and tissues of a murine model of psoriasis, and by in vitro cell culture experiments.ResultsSeveral different immune‐activated cell types with particular cytokine patterns are identified such as keratinocytes, T helper cells, dendritic cells, macrophages and fibroblasts. Apart from well‐known factors, IL‐14 (TXLNA), IL‐18 and IL‐32 are identified with prominent expression in individual cell types in psoriasis. The percentage of inflammatory cellular subtypes expressing IL‐14, IL‐18 and IL‐32 was significantly higher in psoriatic skin compared to healthy control skin. These findings were confirmed by ISH of human skin samples, in a murine model of psoriasis, in human serum samples and in in vitro experiments.ConclusionsTaken together, we provide a differentiated view of psoriasis immune‐cell phenotypes that support a role of IL‐14, IL‐18 and IL‐32 in psoriasis pathogenesis.This article is protected by copyright. All rights reserved

show abstract

“…PDC infiltrates are observed in a great proportion of skin biopsies and can form clusters in CLE skin lesions [ 38 , 40 ]; however, not all skin lesions harbor a pDC infiltrate [ 41 ]. Recently, single-cell ribonucleic acid (RNA) and spatial RNA sequencing has shown that even healthy-appearing skin of CLE patients contains a type I IFN-rich environment and that CD16+ DCs undergo IFN priming in the skin, leading to proinflammatory subtypes [ 42 ]. Because of their central role in CLE pathophysiology, pDCs are an attractive therapeutic target.…”

Section: Pathogenesismentioning

confidence: 99%

Cutaneous Lupus Erythematosus: An Update on Pathogenesis and Future Therapeutic Directions

et al. 2023

View full text Add to dashboard Cite

Lupus erythematosus comprises a spectrum of autoimmune diseases that may affect various organs (systemic lupus erythematosus [SLE]) or the skin only (cutaneous lupus erythematosus [CLE]). Typical combinations of clinical, histological and serological findings define clinical subtypes of CLE, yet there is high interindividual variation. Skin lesions arise in the course of triggers such as ultraviolet (UV) light exposure, smoking or drugs; keratinocytes, cytotoxic T cells and plasmacytoid dendritic cells (pDCs) establish a self-perpetuating interplay between the innate and adaptive immune system that is pivotal for the pathogenesis of CLE. Therefore, treatment relies on avoidance of triggers and UV protection, topical therapies (glucocorticosteroids, calcineurin inhibitors) and rather unspecific immunosuppressive or immunomodulatory drugs. Yet, the advent of licensed targeted therapies for SLE might also open new perspectives in the management of CLE. The heterogeneity of CLE might be attributable to individual variables and we speculate that the prevailing inflammatory signature defined by either T cells, B cells, pDCs, a strong lesional type I interferon (IFN) response, or combinations of the above might be suitable to predict therapeutic response to targeted treatment. Therefore, pretherapeutic histological assessment of the inflammatory infiltrate could stratify patients with refractory CLE for T-cell-directed therapies (e.g. dapirolizumab pegol), B-cell-directed therapies (e.g. belimumab), pDC-directed therapies (e.g. litifilimab) or IFN-directed therapies (e.g. anifrolumab). Moreover, Janus kinase (JAK) and spleen tyrosine kinase (SYK) inhibitors might broaden the therapeutic armamentarium in the near future. A close interdisciplinary exchange with rheumatologists and nephrologists is mandatory for optimal treatment of lupus patients to define the best therapeutic strategy.

show abstract

Nonlesional lupus skin contributes to inflammatory education of myeloid cells and primes for cutaneous inflammation

Cited by 79 publications

References 44 publications

Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems

Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems

Single‐cell transcriptomics reveals prominent expression of IL‐14, IL‐18, and IL‐32 in psoriasis

Cutaneous Lupus Erythematosus: An Update on Pathogenesis and Future Therapeutic Directions

Contact Info

Product

Resources

About