Session Title: 3S077: Pediatric Rheumatology – Basic Science (810–814)
Session Type: ACR Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Macrophage activation syndrome (MAS) is a deadly systemic inflammatory condition marked by an increase in enzymes of iron metabolism including ferritin and heme-oxygenase 1 (HO-1). Since HO-1 has been implicated in anti-inflammatory pathways, we reasoned that drugs that increase HO-1 activity may work to decrease disease activity in MAS. Dimethyl fumarate is an FDA approved drug for the treatment of inflammatory lesions in multiple sclerosis; its active metabolite monomethyl fumarate (MmF) has been shown to increase HO-1 activity. We therefore tested whether MMF could ameliorate MAS in a murine a model of the disease, and to determine its mechanism of action.
Methods: MAS was induced in mice using the well standardized TLR9-MAS protocol. MmF was injected i.p. at a dose of 45 mg/kg twice daily, DMSO injections were used as control. Organs were measured for weight, serum cytokines were measured by ELISA, cellular populations by flow cytometry, and complete blood counts were performed to assess disease activity. C57BL/6 mice were used for all experiments, HO-1 floxed mice bred to LysM-Cre mice (HO-1ΔMac) were used in experiments to test the role of HO-1. HO-1 levels were examined by western blotting. Statistical testing was performed using Student’s T-test or by 2-way ANOVA as appropriate.
Results: HO-1 is upregulated by TLR9 stimulation and is required for the majority of IL-10 induced by TLR9 in vitro and in vivo. Loss of HO-1 by monocytes and macrophages in the HO-1ΔMac mouse did result in lower IL-10 in TLR9-MAS, but did not significantly affect any of the disease parameters. Treatment with MmF increased HO-1 expression in splenic and peritoneal macrophages. Treatment with MmF during TLR9-MAS significantly improved anemia and splenomegaly, and increased serum IL-10 levels while decreasing IFNγ and IL-12 levels. This improvement was significantly, but only partially dependent on HO-1 expression in the monocyte/macrophage compartment as HO-1ΔMac mice were not as protected by MmF therapy as wild type mice during TLR9-MAS.
Conclusion: MmF was effective in reducing a number of disease activity parameters of TLR9-MAS. Furthermore, decreases of the known disease driving cytokines IL-12 and IFNγ were profound. These changes were accompanied an increase in IL-10. We also show that HO-1 plays an important role in regulating IL-10 levels in inflammation, that MmF can increase HO-1 levels, and that the beneficial effects of MmF are partially dependent on HO-1 in the monocyte/macrophage compartment. These results suggest that the parent compound, the FDA approved drug dimethyl fumarate, should be considered in future investigations of MAS therapy, and that pharmacologic manipulation of the HO-1/IL-10 axis may be an important target for future MAS therapies.
To cite this abstract in AMA style:Biswas C, Burn T, Chu N, Behrens E. Monomethyl Fumarate as a Novel Therapy for Macrophage Activation Syndrome: Mechanism of Action in an Animal Model [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/monomethyl-fumarate-as-a-novel-therapy-for-macrophage-activation-syndrome-mechanism-of-action-in-an-animal-model/. Accessed October 25, 2020.
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