High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage.

JCI Insight
Pui Y LeePeter A Nigrovic

Abstract

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication associated with systemic lupus erythematosus, vasculitis, and stem cell transplant. Little is known about the pathophysiology of DAH, and no targeted therapy is currently available. Pristane treatment in mice induces systemic autoimmunity and lung hemorrhage that recapitulates hallmark pathologic features of human DAH. Using this experimental model, we performed high-dimensional analysis of lung immune cells in DAH by mass cytometry and single-cell RNA sequencing. We found a large influx of myeloid cells to the lungs in DAH and defined the gene expression profile of infiltrating monocytes. Bone marrow-derived inflammatory monocytes actively migrated to the lungs and homed adjacent to blood vessels. Using 3 models of monocyte deficiency and complementary transfer studies, we established a central role of inflammatory monocytes in the development of DAH. We further found that the myeloid transcription factor interferon regulatory factor 8 is essential to the development of both DAH and type I interferon-dependent autoimmunity. These findings collectively reveal monocytes as a potential treatment target in DAH.

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Citations

Nov 26, 2020·Clinical Reviews in Allergy & Immunology·Mingming ZhaoQianjin Lu

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Datasets Mentioned

BETA
GSE133083

Methods Mentioned

BETA
flow cytometry
transgenic
confocal microscopy
scRNA-Seq
RNA-Seq
PCR
bronchoalveolar lavage
FCS
FACS

Software Mentioned

GSEA
FCS Express
STAR
viSNE
Loupe Cell Browser
GraphPad
BTL
Prism
Cytobank Premium
SPADE

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