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Am J Physiol Lung Cell Mol Physiol. 2017 Nov 1;313(5):L930-L939. doi: 10.1152/ajplung.00247.2017. Epub 2017 Aug 3.

Alternative pre-mRNA splicing of Toll-like receptor signaling components in peripheral blood mononuclear cells from patients with ARDS.

Author information

1
Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado.
2
Department of Biomedical Research, National Jewish Health, Denver, Colorado.
3
Department of Medicine, National Jewish Health, Denver, Colorado.
4
Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado.
5
Office of the Dean, Wake Forest School of Medicine, Winston-Salem, North Carolina.
6
Department of Biostatistics and Bioinformatics, Colorado School of Public Health, Aurora, Colorado.
7
Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado; alpers@njhealth.org.
8
Program in Mucosal Inflammation and Immunity, National Jewish Health, Denver, Colorado; and.
9
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado.

Abstract

A key physiological feature of acute respiratory distress syndrome (ARDS) is inflammation. Toll-like receptor (TLR) signaling is required to combat the infection that underlies many ARDS cases but also contributes to pathological inflammation. Several TLR signaling pathway genes encoding positive effectors of inflammation also produce alternatively spliced mRNAs encoding negative regulators of inflammation. An imbalance between these isoforms could contribute to pathological inflammation and disease severity. To determine whether splicing in TLR pathways is altered in patients with ARDS, we monitored alternative splicing of MyD88 and IRAK1, two genes that function in multiple TLR pathways. The MyD88 and IRAK1 genes produce long proinflammatory mRNAs (MyD88L and IRAK1) and shorter anti-inflammatory mRNAs (MyD88S and IRAK1c). We quantified mRNA encoding inflammatory cytokines and MyD88 and IRAK1 isoforms in peripheral blood mononuclear cells (PBMCs) from 104 patients with ARDS and 30 healthy control subjects. We found that MyD88 pre-mRNA splicing is altered in patients with ARDS in a proinflammatory direction. We also observed altered MyD88 isoform levels in a second critically ill patient cohort, suggesting that these changes may not be unique to ARDS. Early in ARDS, PBMC IRAK1c levels were associated with patient survival. Despite the similarities in MyD88 and IRAK1 alternative splicing observed in previous in vitro studies, there were differences in how MyD88 and IRAK1 alternative splicing was altered in patients with ARDS. We conclude that pre-mRNA splicing of TLR signaling genes is altered in patients with ARDS, and further investigation of altered splicing may lead to novel prognostic and therapeutic approaches.

KEYWORDS:

IRAK1; MyD88; acute respiratory distress syndrome; alternative pre-mRNA splicing; inflammation; peripheral blood mononuclear cell

PMID:
28775099
PMCID:
PMC5792175
DOI:
10.1152/ajplung.00247.2017
[Indexed for MEDLINE]
Free PMC Article

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