Background/Purpose: Macrophage activation syndrome (MAS) is a life-threatening cytokine storm syndrome frequently complicating systemic juvenile idiopathic arthritis (SJIA) and driven by IFNγ. MAS is also associated with an emerging and severe inflammatory lung disease (SJIA-LD). The causes and pathogenesis of SJIA-LD are unknown, but have been proposed to include introduction of anti-cytokine therapies, allergic reactions, or other environmental factors, along with recurrent MAS. Our recent work supports activation of IFNγ pathways in the lungs of children with SJIA-LD, supporting a pathologic link between pulmonary inflammation and MAS. The objective of this study was to mechanistically define the novel observation of pulmonary inflammation in the TLR9 mouse model of MAS.

Methods: Pulmonary inflammation was examined by histopathology, cytokine/chemokine levels and alveolar macrophage gene expression profiling. IFNγ signaling was inhibited through neutralizing antibodies as well as using mice with macrophages insensitive to IFNγ.

Results: In acute MAS, lungs exhibit mild but diffuse lymphocyte-predominant, primarily perivascular interstitial inflammation with elevated IFNγ, elevated levels of the IFN-induced chemokines CXCL9 and CXCL10, and alveolar macrophage expression of IFNγ-induced genes. We have further developed the TLR9 model system by for the first time characterizing the resolution phase of MAS. MAS resolution was associated with alveolar macrophage expansion and increased interstitial mononuclear cell infiltration. Alveolar macrophage microarrays confirmed IFNγ-induced proinflammatory polarization during acute MAS. However, this switches towards an anti-inflammatory phenotype during MAS resolution with activation of STAT6-induced genes and repression of STAT1-induced genes. As many patients with SJIA-LD have repeated episodes of MAS, we retreated mice with CpG to model recurrent MAS. Interestingly, recurrent MAS led to increased alveolar inflammation, and reset alveolar macrophage polarization towards a persistent proinflammatory state. Furthermore, using both direct IFNg blockade and macrophages insensitive to IFNγ (MIIG) mice, both systemic feature of MAS and pulmonary inflammation were markedly attenuated.

Conclusion: These findings demonstrate that experimental MAS induces IFNγ-driven pulmonary inflammation that replicates key features of children with SJIA-LD. These findings support a model whereby MAS induces IFNγ-driven pulmonary inflammation and dynamic changes in alveolar macrophage polarization, contributing to development of SJIA-LD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ifn%ce%b3-is-essential-for-alveolar-macrophage-driven-lung-inflammation-in-macrophage-activation-syndrome/