Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases
Satish Sati, … , Misha Rosenbach, Thomas H. Leung
Satish Sati, … , Misha Rosenbach, Thomas H. Leung
Published September 3, 2024
Citation Information: J Clin Invest. 2024;134(17):e178711. https://doi.org/10.1172/JCI178711.
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Research Article Dermatology Immunology

Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases

Abstract

Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling. Lung sarcoidosis granulomas also displayed similar immune cell recruitment. Thus, granuloma formation was not a generic molecular response. In addition to tissue-specific effects, patients with sarcoidosis exhibited an 8-fold increase in circulating ILC1s, which correlated with treatment status. Multiple immune cell types induced CXCL12/CXCR4 signaling in sarcoidosis, including Th1 T cells, macrophages, and ILCs. Mechanistically, CXCR4 inhibition reduced sarcoidosis-activated immune cell migration, and targeting CXCR4 or total ILCs attenuated granuloma formation in a noninfectious mouse model. Taken together, our results show that ILC1s are a tissue and circulating biomarker that distinguishes sarcoidosis from other skin granulomatous diseases. Repurposing existing CXCR4 inhibitors may offer a new targeted treatment for this devastating disease.

Authors

Satish Sati, Jianhe Huang, Anna E. Kersh, Parker Jones, Olivia Ahart, Christina Murphy, Stephen M. Prouty, Matthew L. Hedberg, Vaibhav Jain, Simon G. Gregory, Denis H. Leung, John T. Seykora, Misha Rosenbach, Thomas H. Leung

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Figure 3

Sarcoid granulomas contain ILC1s and B cell aggregates.

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Sarcoid granulomas contain ILC1s and B cell aggregates. (A) Deconvoluted...
(A) Deconvoluted cell type identification from spatial transcriptomics of patients with sarcoidosis (n = 2) and non-sarcoidosis granuloma (n = 1) patients. Each spot is represented as a pie chart displaying relative cell proportions. The middle panel highlights individual immune cell populations and the right panel highlights ILCs specifically. (B and C) Ligand-receptor analysis of spatial transcriptomics data sets for patients with sarcoidosis and non-sarcoidosis patients. Color represents signaling intensity. (D) Representative immunohistochemistry (n = 7 patients) depicting localization of B cells (CD20, PAX5), T cells (CD3), and macrophages (CD68) in sarcoidosis-affected skin. Dotted box outlines sarcoid granuloma. (E) Representative histology (n = 3 patients) depicting localization of mature germinal center–like B cells (CD3–CD20+CD23+, white arrows). Scale bars: 50 μm and 5 μm (yellow insets). (F) Representative histology (n = 3 patients) depicting localization of ILC1 (Lin–IL7R+Tbet+, white arrowheads). Lineage– = CD3–CD16–CD19–CD20–CD56–CD68– (labeled in green). Scale bars: 100 μm and 10 μm (insets).