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 Article has an altmetric score of 33

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 5

Blood from patients with sarcoidosis contains increased circulating levels of ILC1s.

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Blood from patients with sarcoidosis contains increased circulating leve...
(A) Identification of cell clusters from blood of patients with sarcoidosis (S, n = 7) and healthy volunteers (HV, n = 6). (B) Scatter plot shows relative contribution of ILCs as percentage of total cells. Statistical significance was calculated using 2-tailed, unpaired Student’s t test. (C) Flow cytometry analysis of ILC subtypes as percentage of total CD45+ cells in healthy volunteers (n = 17), non-sarcoidosis granuloma patients (G, n = 5), and sarcoidosis patient blood (n = 13). One-way ANOVA revealed statistical significance for ILC1: F(2,27) = 19, *P < 0.05, ***P < 0.001; ILC2 and ILC3 were not significant among groups. (D) Receiver operating characteristic (ROC) curves for ILC1 (red) and ILC3 (black) from sarcoidosis patient PBMCs. Area under the curve (AUC) values are listed. (E) Flow cytometry analysis of ILC subtypes as percentage of total CD45+ cells in blood from no-treatment patients (n = 7), treated sarcoid patients (n = 6), and healthy volunteers (n = 17). One-way ANOVA revealed statistical significance for ILC1: F(2,27) = 55, ***P < 0.001; ILC2 and ILC3 are not significant. (F) Comparison of gene expression from bulk RNA-seq analysis of flow cytometry–purified sarcoidosis skin ILC1s (n = 2), sarcoidosis blood ILC1s (n = 2), and healthy volunteer ILC1s (n = 3). (G) Volcano plot of pathway analysis comparing flow cytometry–purified ILC1s from sarcoidosis blood and healthy volunteer blood. Data represented as mean ± SEM. NS, not significant. UPR, unfolded protein response; Ox phos, oxidative phosphorylation.