Alveolar macrophage gene expression in a mouse model of MAS

Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (SJIA), and increasingly reported in association with severe lung disease (SJIA-LD) of unknown etiology. This study mechanistically defines the novel observation of pulmonary inflammation in the TLR9 mouse model of MAS that recapitulate key features of SJIA-LD, including IFNg activation. In acute MAS, lungs exhibit a mild but diffuse lymphocyte-predominant perivascular, interstitial inflammation with elevated IFNg, IFN-induced chemokines, and alveolar macrophage (AMf) expression of IFNg-induced genes. However, MAS resolution demonstrated AMf expansion and increased interstitial inflammation. AMf microarrays confirmed IFNg-induced proinflammatory polarization during acute MAS, which switches towards anti-inflammatory phenotype during MAS resolution. Interestingly, recurrent MAS increased alveolar inflammation, and reset polarization towards a pro-inflammatory state. Furthermore, in mice bearing macrophages insensitive to IFNg, both systemic feature of MAS and pulmonary inflammation were markedly attenuated. These findings demonstrate experimental MAS induces IFNg-driven pulmonary inflammation, and define this system for further study of and treatment validation in SJIA-LD. We used microarrays to study whole transcriptome analysis of alveolar macrophages in the TLR9 mouse model of MAS during both acute MAS and MAS resolution. 11 mice were given 5 injections over 10 days with vehicle (PBS) or CpG. BAL fluid was obtained on day 10 (acute MAS) or day 30 (MAS resolution). Alveolar macrophages were purified by adherence, and RNA extraction for hybridization on Affymetrix microarrays.