Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome
Yale Jiang, Brian R. Rosborough, Jie Chen, Sudipta Das, Georgios D. Kitsios, Bryan J. McVerry, Rama K. Mallampalli, Janet S. Lee, Anuradha Ray, Wei Chen, Prabir Ray
Yale Jiang, Brian R. Rosborough, Jie Chen, Sudipta Das, Georgios D. Kitsios, Bryan J. McVerry, Rama K. Mallampalli, Janet S. Lee, Anuradha Ray, Wei Chen, Prabir Ray
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Research Article Immunology Pulmonology

Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome

Abstract

Acute respiratory distress syndrome (ARDS) results from overwhelming pulmonary inflammation. Prior bulk RNA sequencing provided limited insights into ARDS pathogenesis. We used single cell RNA sequencing to probe ARDS at a higher resolution. PBMCs of patients with pneumonia and sepsis with early ARDS were compared with those of sepsis patients who did not develop ARDS. Monocyte clusters from ARDS patients revealed multiple distinguishing characteristics in comparison with monocytes from patients without ARDS, including downregulation of SOCS3 expression, accompanied by a proinflammatory signature with upregulation of multiple type I IFN–induced genes, especially in CD16+ cells. To generate an ARDS risk score, we identified upregulation of 29 genes in the monocytes of these patients, and 17 showed a similar profile in cells of patients in independent cohorts. Monocytes had increased expression of RAB11A, known to inhibit neutrophil efferocytosis; ATP2B1, a calcium pump that exports Ca2+ implicated in endothelial barrier disruption; and SPARC, associated with processing of procollagen to collagen. These data show that monocytes of ARDS patients upregulate expression of genes not just restricted to those associated with inflammation. Together, our findings identify molecules that are likely involved in ARDS pathogenesis that may inform biomarker and therapeutic development.

Authors

Yale Jiang, Brian R. Rosborough, Jie Chen, Sudipta Das, Georgios D. Kitsios, Bryan J. McVerry, Rama K. Mallampalli, Janet S. Lee, Anuradha Ray, Wei Chen, Prabir Ray

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Figure 5

Differential gene expression in monocytes can distinguish between sepsis-only and sepsis+ARDS patients.

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Differential gene expression in monocytes can distinguish between sepsis...
(A) Heatmap showing expression levels and weights assigned to each of the 29 genes that distinguish between patients with sepsis only (n = 8) and those with sepsis+ARDS (n = 26) in our scRNA-seq data as compared with microarray gene expression data of peripheral blood monocytes that were publicly available in 2 data sets. Asterisks indicate genes upregulated in both the scRNA-seq data set and publicly available data sets. (B and C) Comparison between groups using the ARDS risk score comprising 29 genes (B) versus a random selection of genes (C). Box-and-whisker plots show the median (bar) with IQR (box) and upper/lower limit within 1.5 IQRs from the box range (whiskers). The red dot indicates the mean of the score values. In B, values of the box plot for scores of sepsis-only patients are: minimum = –0.23, lower = –0.19, middle = –0.18, upper = –0.15, maximum = –0.15. For sepsis+ARDS patients: minimum = –0.11, lower = –0.09, middle = –0.08, upper = –0.07, maximum = –0.05. In C, values of the box plot for scores of sepsis-only patients are: minimum = –0.29, lower = –0.12, middle = –0.01, upper = 0.11, maximum = 0.26. For sepsis+ARDS patients: minimum = –0.26, lower = –0.14, middle = –0.04, upper = 0.06, maximum = 0.31. Two-tailed Student’s t test was applied.