Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases
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
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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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 4

Sarcoid granulomas exhibit molecular features resembling mature tertiary lymphoid structures.

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Sarcoid granulomas exhibit molecular features resembling mature tertiary...
(A) Global analysis of ligand-receptor pathways between sarcoid and non-sarcoid granulomas. Arrows highlight TNF family and CCL signaling. (B) Cell-specific ligand-receptor analysis. Bottom half of circle depicts secreting cell types, and upper half of circle depicts receiving cell types. Inner bottom circle is a summary of the receiving cell types. (C) Dot plot demonstrating average expression (color) and percentage of cells (dot size) expressing specific cytokines. (D) Volcano plot of differential gene expression for sarcoidosis and non-sarcoidosis fibroblasts depicting increased CCL19 and CXCL13 expression. (E) Volcano plot of differential gene expression from bulk RNA-seq of isolated ILC1s from sarcoidosis skin (n = 2) vs. sarcoidosis blood (n = 2), demonstrating increased expression of CCL19 and CXCR4 in skin ILCs. (F) Density plot demonstrating that sarcoidosis-specific B cells express MS4A1 (CD20) and FCER2 (CD23) markers. (G) Summary of unique ligand-receptor interactions found in sarcoid granulomas.