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Updated: Sep 1, 2025
An IL-8 Transiently Transgenized Mouse Model for the In Vivo Long-term Monitoring of Inflammatory Responses
Published on: July 7, 2017
MDA5 signaling induces type 1 IFN- and IL-1-dependent lung vascular permeability which protects mice from
Michael J Davis1, Rachel E Martin1, Giovana M Pinheiro1
1Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.
Abstract:
Lungs balance threat from primary viral infection, secondary infection, and inflammatory damage. Severe pulmonary inflammation induces vascular permeability, edema, and organ dysfunction. We previously demonstrated that poly(I:C) (pICLC) induced type 1 interferon (t1IFN) protected mice from Cryptococcus gattii (Cg) via local iron restriction. Here we show pICLC increased serum protein and intravenously injected FITC-dextran in the lung airspace suggesting pICLC induces vascular permeability. Interestingly, pICLC induced a pro-inflammatory signature with significant expression of IL-1 and IL-6 which depended on MDA5 and t1IFN. Vascular permeability depended on MDA5, t1IFN, IL-1, and IL-6. T1IFN also induced MDA5 and other MDA5 signaling components suggesting that positive feedback contributes to t1IFN dependent expression of the pro-inflammatory signature. Vascular permeability, induced by pICLC or another compound, inhibited Cg by limiting iron. These data suggest that pICLC induces t1IFN which potentiates pICLC-MDA5 signaling increasing IL-1 and IL-6 resulting in leakage of antimicrobial serum factors into lung airspace. Thus, induced vascular permeability may act as an innate defense mechanism against opportunistic fungal infection, such as cryptococcosis, and may be exploited as a host-directed therapeutic target.
Insights
Poly(I:C) (pICLC) induces vascular permeability in the lungs, enhancing innate immunity against fungal infections like cryptococcosis by restricting iron availability.
Area of Science:
- Immunology
- Pulmonary Medicine
- Infectious Diseases
Background:
- The lungs face threats from viral infections, secondary infections, and inflammation.
- Severe lung inflammation can lead to increased vascular permeability, edema, and organ dysfunction.
- Previous studies showed poly(I:C) (pICLC) induced type 1 interferon (t1IFN) protected mice against *Cryptococcus gattii* (Cg) via iron restriction.
Purpose of the Study:
- To investigate the mechanisms by which pICLC affects lung vascular permeability and its role in innate immunity.
- To determine the signaling pathways involved in pICLC-induced vascular permeability and inflammation.
- To explore the potential of induced vascular permeability as a host-directed therapeutic strategy against fungal infections.
Main Methods:
- Mice were treated with pICLC to assess lung vascular permeability using serum protein and FITC-dextran leakage.
- Gene expression analysis was performed to identify inflammatory signatures, focusing on IL-1, IL-6, and MDA5.
- The roles of MDA5, t1IFN, IL-1, and IL-6 in vascular permeability were investigated.
- The impact of pICLC-induced vascular permeability on Cg fungal burden was evaluated.
Main Results:
- pICLC treatment increased lung vascular permeability, evidenced by elevated serum protein and FITC-dextran in the lung airspace.
- pICLC induced a pro-inflammatory response characterized by increased IL-1 and IL-6 expression, dependent on MDA5 and t1IFN.
- Vascular permeability was found to be dependent on MDA5, t1IFN, IL-1, and IL-6.
- Positive feedback loops involving t1IFN and MDA5 signaling were suggested to enhance the pro-inflammatory response.
- pICLC-induced vascular permeability inhibited Cg growth by limiting iron availability.
Conclusions:
- pICLC induces t1IFN, which potentiates MDA5 signaling, leading to increased IL-1 and IL-6 production.
- This results in enhanced vascular permeability and the leakage of antimicrobial factors into the lung airspace.
- Induced vascular permeability may serve as an innate defense mechanism against opportunistic fungal infections like cryptococcosis.
- This mechanism presents a potential host-directed therapeutic target for managing fungal infections.
