Myeloid heme oxygenase-1 deficiency exacerbates TLR7-induced lupus 2136

Abstract Description Background The immunogenicity of monocytes is upregulated in systemic lupus erythematosus (SLE). However, the underlying mechanisms remain obscure. Heme oxygenase-1 (HO-1, coded by the HMOX-1 gene) is an anti-inflammatory enzyme that controls monocyte function. Compared to controls, HO-1 levels in SLE patients’ monocytes are significantly reduced. In this study, we investigated the outcomes of TLR-7-induced lupus in mice harboring HO-1 deficiency in their myeloid compartment (Hmox-1Lysm-/-). Methods Female Hmox-1Lysm-/- and littermate controls (WT) were treated epicutaneously with R848 (TLR7 agonist) for 5 weeks and outcomes were analyzed. The response of bone marrow-derived macrophages (BMDM) from both strains to R848 was compared. Results Compared to WT, Hmox-1Lysm-/- mice had significantly higher numbers of monocytes, DCs, and activated CD4+ T cells in the spleen and kidneys. Some of the cells were identified as histiocytes. The immune infiltrates in Hmox-1Lysm-/- mice had a periglomerular and interstitial distribution, but a-dsDNA IgG levels and immune complex deposits were similar between strains. R848-stimulated Hmox-1Lysm-/- BMDM had a higher expression of NFkB and produced more TNFa and IL-6 than WT cells. Conclusion A gain-of-function mutation in TLR7 or heightened TLR7 signaling is directly linked to the development of human lupus. Our data emphasizes the need for strategies to increase HO-1 in SLE myeloid cells to attenuate TLR-7-induced pathology in lupus. Funding Sources Supported by NIH (R01DK136011) to Y. Scindia and L. Morel. Vifor Pharma (P0213104) to Y. Scindia. Topic Categories Immune Mechanisms of Human Disease (HUM)