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 7

CXCR4 is necessary for ILC1 migration and mouse noninfectious granuloma formation.

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CXCR4 is necessary for ILC1 migration and mouse noninfectious granuloma ...
(A) Dot plot comparing cytokine ligand and receptor gene expression in sarcoidosis and skin inflammatory diseases. Dot size reflects percentage cells expressing the gene, and color illustrates level of gene expression. MC, molluscum contagiosum; BP, bullous pemphigoid; AE, acrodermatitis enteropathica; AD, atopic dermatitis. (B) Representative spatial transcriptomics depicting CXCR4 and CXCL12 expression in affected sarcoidosis (n = 2), unaffected sarcoidosis (n = 2), psoriasis (n = 3), and healthy volunteer skin (n = 3). (C) Representative immunohistochemistry (n = 3) of CXCL12 depicting expression within sarcoid granulomas. Scale bars: 50 μm. (D) Fold change in CXCL12-mediated migration of CD45+ immune cells from healthy volunteers (HV, n = 4) and sarcoidosis blood (n = 4) with and without CXCR4 inhibitor (plerixafor). Mean ± SEM. Significance was calculated by 2-tailed, paired Student’s t test. (E) H&E staining highlighting pulmonary granuloma formation in lung tissue from cadmium nanoparticle–induced mice treated with PBS or plerixafor. Scale bars: 100 μm. Quantification of lung granuloma formation (n = 5 in each group). Data represented as scatter plots show mean ± SEM. *P < 0.05; ***P < 0.001 by 2-tailed, unpaired Student’s t test.