Reducing hypoxia and inflammation during invasive pulmonary aspergillosis by targeting the Interleukin-1 receptor
Mark S Gresnigt1,2, Abdessalem Rekiki3, Orhan Rasid1
1Unité de recherche Cytokines &Inflammation, Institut Pasteur, Paris.
Abstract:
Hypoxia as a result of pulmonary tissue damage due to unresolved inflammation during invasive pulmonary aspergillosis (IPA) is associated with a poor outcome. Aspergillus fumigatus can exploit the hypoxic microenvironment in the lung, but the inflammatory response required for fungal clearance can become severely disregulated as a result of hypoxia. Since severe inflammation can be detrimental to the host, we investigated whether targeting the interleukin IL-1 pathway could reduce inflammation and tissue hypoxia, improving the outcome of IPA. The interplay between hypoxia and inflammation was investigated by in vivo imaging of hypoxia and measurement of cytokines in the lungs in a model of corticosteroid immunocompromised and in Cxcr2 deficient mice. Severe hypoxia was observed following Aspergillus infection in both models and correlated with development of pulmonary inflammation and expression of hypoxia specific transcripts. Treatment with IL-1 receptor antagonist reduced hypoxia and slightly, but significantly reduced mortality in immunosuppressed mice, but was unable to reduce hypoxia in Cxcr2(-/-) mice. Our data provides evidence that the inflammatory response during invasive pulmonary aspergillosis, and in particular the IL-1 axis, drives the development of hypoxia. Targeting the inflammatory IL-1 response could be used as a potential immunomodulatory therapy to improve the outcome of aspergillosis.
Insights
Targeting the IL-1 pathway in invasive pulmonary aspergillosis (IPA) reduced hypoxia and mortality in mice. This suggests the IL-1 axis drives hypoxia, offering a potential immunomodulatory therapy for IPA.
Area of Science:
- Medical research
- Immunology
- Pulmonology
Background:
- Invasive pulmonary aspergillosis (IPA) involves lung tissue damage and inflammation, leading to hypoxia and poor outcomes.
- Hypoxia exacerbates inflammation during IPA, creating a detrimental cycle for the host.
- The role of the interleukin-1 (IL-1) pathway in this hypoxia-inflammation interplay is not fully understood.
Purpose of the Study:
- To investigate if targeting the IL-1 pathway can reduce inflammation and tissue hypoxia in IPA.
- To determine if modulating IL-1 signaling improves outcomes in a mouse model of IPA.
Main Methods:
- Utilized in vivo imaging to assess hypoxia and measured cytokine levels in the lungs of corticosteroid-immunocompromised and Cxcr2-deficient mice infected with Aspergillus.
- Administered IL-1 receptor antagonist to evaluate its effects on hypoxia and mortality.
Main Results:
- Severe hypoxia was observed in both mouse models following Aspergillus infection, correlating with pulmonary inflammation.
- Treatment with an IL-1 receptor antagonist reduced hypoxia and significantly decreased mortality in immunosuppressed mice.
- The IL-1 receptor antagonist did not reduce hypoxia in Cxcr2-deficient mice, indicating a role for this pathway.
Conclusions:
- The inflammatory response, specifically the IL-1 axis, drives hypoxia development during invasive pulmonary aspergillosis.
- Targeting the IL-1 inflammatory response presents a potential immunomodulatory therapy to improve outcomes in IPA.
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