Extracellular RNA facilitates hypoxia-induced leukocyte adhesion and infiltration in the lung through TLR3-IFN-γ-STAT1 signaling pathway.
Endogenous ligands released from dying cells, including extracellular RNA (eRNA), cause TLR activation, which is associated with inflammation and vascular diseases. However, the importance of this response in acute hypoxia (AH) remains unexplored. Here, we observed eRNA-mediated TLR3 activation during exposure of mice to AH in the absence of exogenous viral stimuli. RNaseA treatment diminished AH-induced expression of IFN and cell adhesion molecules (CAMs) and myeloid cell infiltration in the lung, and TLR3 gene silencing or neutralization with antibodies markedly attenuated AH- or poly I:C-induced IFN and CAM expression and leukocyte adhesion (LA) and myeloid cell infiltration in the lung. However, RNaseA treatment or TLR3 gene silencing failed to alter AH-induced cell death and proliferation in lung vasculature. Furthermore, IFN-γ--but not IFN-α--regulated AH-induced CAM expression and LA. Treatment with RNaseA, TLR3 siRNA, neutralizing antibodies, or a STAT1 inhibitor substantially decreased AH- and poly I:C-induced STAT1 phosphorylation, CAM expression, and myeloid cell infiltration, suggesting a central role for STAT1 phosphorylation in AH-induced LA and infiltration. We conclude that eRNA activates TLR3 and facilitates, through in vivo IFN-γ-STAT1 signaling, AH-induced leukocyte infiltration in the lung. Thus, RNaseA might provide a therapeutic alternative for patients with lung diseases.
Department of Physiology, Defence Institute of Physiology and Allied Sciences, Timarpur, Delhi, India.
Indranil
I
Biswas
Department of Physiology, Defence Institute of Physiology and Allied Sciences, Timarpur, Delhi, India.
Bandana
B
Singh
Department of Proteomics, Defence Institute of Physiology and Allied Sciences, Timarpur, Delhi, India.
Manish
M
Sharma
Institute of Nuclear Medicine and Allied Sciences, Timarpur, Delhi, India.
Paban K
PK
Agrawala
Department of Physiology, Defence Institute of Physiology and Allied Sciences, Timarpur, Delhi, India.
Gausal A
GA
Khan
D000818:Animals; D015153:Blotting, Western; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D000860:Hypoxia / Q000276:immunology / Q000473:pathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000473:pathology*; D051379:Mice; D012313:RNA / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism
D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D012313:RNA; D007371:Interferon-gamma
Acute hypoxia; Extracellular RNA; ICAM1; STAT1; TLR3