IFN-γ is essential for alveolar macrophage-driven pulmonary inflammation in macrophage activation syndrome
Denny K Gao1, Nathan Salomonis2,3, Maggie Henderlight1
1Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Abstract:
Macrophage activation syndrome (MAS) is a life-threatening cytokine storm complicating systemic juvenile idiopathic arthritis (SJIA) driven by IFN-γ. SJIA and MAS are also associated with an unexplained emerging inflammatory lung disease (SJIA-LD), with our recent work supporting pulmonary activation of IFN-γ pathways pathologically linking SJIA-LD and MAS. Our objective was to mechanistically define the potentially novel observation of pulmonary inflammation in the TLR9 mouse model of MAS. In acute MAS, lungs exhibit mild but diffuse CD4-predominant, perivascular interstitial inflammation with elevated IFN-γ, IFN-induced chemokines, and alveolar macrophage (AMϕ) expression of IFN-γ-induced genes. Single-cell RNA sequencing confirmed IFN-driven transcriptional changes across lung cell types with myeloid expansion and detection of MAS-specific macrophage populations. Systemic MAS resolution was associated with increased AMϕ and interstitial lymphocytic infiltration. AMϕ transcriptomic analysis confirmed IFN-γ-induced proinflammatory polarization during acute MAS, which switches toward an antiinflammatory phenotype after systemic MAS resolution. Interestingly, recurrent MAS led to increased alveolar inflammation and lung injury, and it reset AMϕ polarization toward a proinflammatory state. Furthermore, in mice bearing macrophages insensitive to IFN-γ, both systemic features of MAS and pulmonary inflammation were attenuated. These findings demonstrate that experimental MAS induces IFN-γ-driven pulmonary inflammation replicating key features of SJIA-LD and provides a model system for testing potentially novel treatments directed toward SJIA-LD.
Insights
Macrophage activation syndrome (MAS) drives lung inflammation via interferon-gamma (IFN-γ) in a mouse model. This research reveals a new model for studying MAS-associated lung disease and potential treatments.
Area of Science:
- Immunology
- Pulmonology
- Rheumatology
Background:
- Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile idiopathic arthritis (SJIA), characterized by a cytokine storm.
- Emerging evidence links SJIA and MAS to an unexplained inflammatory lung disease (SJIA-LD), with interferon-gamma (IFN-γ) pathways implicated in both conditions.
- Pulmonary inflammation in SJIA-LD and MAS remains mechanistically undefined.
Purpose of the Study:
- To investigate the mechanistic basis of pulmonary inflammation in a mouse model of MAS.
- To define the role of IFN-γ in experimental MAS-induced lung disease.
- To establish a preclinical model for testing novel therapies for SJIA-LD.
Main Methods:
- Utilized a Toll-like receptor 9 (TLR9) mouse model of MAS.
- Analyzed lung tissue for inflammatory cell infiltration and gene expression.
- Performed single-cell RNA sequencing (scRNA-seq) on lung cells.
- Assessed macrophage polarization and function.
- Investigated the impact of IFN-γ-insensitive macrophages on MAS and lung inflammation.
Main Results:
- Acute MAS induced CD4+ T cell-predominant interstitial lung inflammation with elevated IFN-γ and IFN-γ-induced genes in alveolar macrophages (AMϕ).
- scRNA-seq revealed IFN-γ-driven transcriptional changes, myeloid expansion, and distinct MAS-associated macrophage populations in the lungs.
- AMϕ exhibited a proinflammatory IFN-γ-driven phenotype during acute MAS, switching to an anti-inflammatory state upon resolution; recurrent MAS led to persistent inflammation and lung injury.
- Mice with IFN-γ-insensitive macrophages showed attenuated systemic MAS and pulmonary inflammation.
Conclusions:
- Experimental MAS recapitulates key features of SJIA-LD, driven by IFN-γ-mediated pulmonary inflammation.
- Alveolar macrophages play a critical role in the pathogenesis of MAS-induced lung disease, with dynamic polarization shifts.
- This study provides a valuable preclinical model for understanding and developing targeted therapies for SJIA-LD.
