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 1

Immune cell landscape in sarcoidosis and non-sarcoidosis skin granulomas.

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Immune cell landscape in sarcoidosis and non-sarcoidosis skin granulomas...
(A) Overview of sample collection. (B) Identification of cell clusters from patients with sarcoidosis (n = 18 for affected and n = 18 unaffected skin) and non-sarcoidosis skin granuloma patients (n = 10 for affected and n = 9 unaffected skin). VE, vascular endothelium; LE, lymphatic endothelium. (C) UMAP depicting subclustering of immune cells. pDC, plasmacytoid DC; cDC, conventional DC. (D) Marker genes defining immune subsets. Dot size reflects percentage cells expressing the gene, and color illustrates level of gene expression. (E) Box-and-whisker plot shows relative contribution of immune cells as percentage of total cells. In the box-and-whisker plot, the box extends from the 25th to 75th percentile. The line in the middle of the box represents the median, and the whiskers represent the minimum and maximum. All data points are covered, no outlying values. Statistical significance was calculated using a 2-tailed Student’s t test. (F) Dot plot depicting gene activation in different immune clusters. Dot size reflects percentage cells expressing the gene, and color illustrates level of gene expression. Data depicted as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.