Background/Purpose: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is a life-threatening complication and associated in >80% of cases with macrophage activation syndrome (MAS); however, the underlying disease mechanisms driving lung inflammation are unknown. We have previously shown that the TLR9-stimulated mouse model of MAS demonstrates IFNγ-driven lung inflammation replicating several key features of SJIA-LD. Our objective was to determine the evolution of lung inflammation in a TLR9-stimulated mouse model of chronic/recurrent MAS.

Methods: C57BL/6J mice were intraperitoneal injected 5 times with CpG over 10 days, with 10 days following cycles, yielding mice with acute MAS (1 cycle of CpG), recovery (10 days after one cycle), or chronic/recurrent MAS (3 cycles of CpG). Blood, Bronchoalveolar lavage (BAL), lung and spleen were collected. Lungs were digested, stained and analyzed for flow cytometry.

Results: Compared to mice with acute MAS, mice with chronic/recurrent MAS demonstrated largely similar findings of anemia, thrombocytopenia, lymphopenia, splenomegaly, and serum and BAL cytokine elevations. In order to quantify changes in lung monocyte and macrophage populations, we examined whole lung digests using Flow cytometry. During acute MAS we found significantly higher proportions of neutrophils, interstitial macrophages, and less mature monocytes and macrophages in the lungs. During MAS recovery however, most cell populations normalized except for a persistent increase in both Ly6C- and Ly6C+/SiglecF- monocytes and macrophages. With chronic/recurrent MAS, we observed more marked alterations in the myeloid compartment, including significant decrease in CD11bLo/SiglecF+ alveolar macrophages and increase in CD11b+/SiglecF- macrophages, as well as increases in both CD11b+ conventional dendritic cells (DCs) and CD103+ pulmonary DCs and marked absence of eosinophils. In order to determine how the alveolar inflammatory environment changed during chronic/recurrent MAS, we performed proteomics from BAL fluid using Somalogic. Compared to control (PBS-treated mice), in mice with chronic/recurrent MAS we identified 119 proteins with increased abundance and 91 proteins with decreased abundance. These included significantly increased BAL levels of IL-1A, IL-16, IL-18BP, IL-33, and TGFA. Interestingly, most proteins with increased abundance (72%) were not significantly different during acute MAS. Using GO-Elite, we found Complement and Coagulation Cascade to be the most highly enriched KEGG pathway among proteins with increased abundance in chronic/recurrent MAS (z-score 9.37, adjusted p=9.14×10-5).

Conclusion: In a mouse model of chronic/recurrent MAS, we see persistent alternations in lung myeloid populations including replacement of CD11bLo/SiglecF+ alveolar macrophages with CD11b+/SiglecF- macrophages, and increasing levels of pro-inflammatory and pro-fibrotic cytokines with activation of the complement and coagulation pathways in BAL. Together, this work supports persistent alternations in the lung inflammatory environment driven by chronic/recurrent MAS, with important implications for the development of SJIA-LD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evolution-of-lung-inflammation-in-a-mouse-model-of-chronic-recurrent-macrophage-activation-syndrome/