The pathogenesis of systemic lupus erythematosus (SLE) and cardiovascular disease (CVD) are tightly linked, and CVD is one of the leading causes of death in lupus patients. There are many risk factors that increase the risk of CVD in SLE patients, including endothelial dysfunction, lipid dysregulation, and abnormal regulation of innate and adaptive immunity. We have previously investigated the role of interferon regulatory factor 5 (Irf5), on atherosclerosis in lupus mouse models. Irf5 has a pro-inflammatory function by activating macrophage and cytokine recruitment and is thus being considered as a potential therapeutic target for the treatment of SLE. We hypothesized that Irf5 deficiency would ameliorate lupus disease as well as improve cardiovascular disease in the Irf5-deficient mouse model. However, while lupus disease did improve in the mouse model, the atherosclerotic plaques were found to be significantly increased in size. This poses a challenge to our current understanding of Irf5, as well as adds complexity to an already difficult clinical problem. Therefore, our aim of this study is to characterize the cells within the atherosclerotic lesions to examine their inflammatory potential. The focus of this study is the infiltration of macrophages into the mouse aortic root as determined by immunohistochemistry staining.
In a time-course study using apoE.Irf5-/- mice, we found that macrophages started to accumulate into aortic leaflets as early as two weeks after starting a Western diet. Macrophage infiltration into the site of leaflet attachment seemed to possibly be a precursor to atherosclerotic lesion formation and appeared as early as 4 weeks after starting Western diet. No apparent differences were found between Irf5 sufficient and Irf5 deficient mice at either two or four weeks on Western diet.
In a bone marrow chimera study, we examined the effects of Irf5 from bone marrow- and non-bone marrow-derived cells on the accumulation of macrophages on aortic leaflets and in the tunica intima in the gld.apoE-/- mouse model of lupus and atherosclerosis. Macrophage accumulation did not correlate with differences in Irf5 production. However, the finding of macrophage accumulation on aortic leaflets suggests a role of macrophages in Libman-Sacks endocarditis, an inflammatory disease of the mitral and aortic valves seen in patients with lupus.
Together, our results do not support nor refute a role of Irf5 in macrophage infiltration into the aortic root. More samples are needed, as are more methods of identifying macrophages and quantifying them. However, it is still likely that macrophages play a role in the pathogenesis of atherosclerotic lesion formation in a lupus mouse model, and it is an area of study worth exploring.
In a time-course study using apoE.Irf5-/- mice, we found that macrophages started to accumulate into aortic leaflets as early as two weeks after starting a Western diet. Macrophage infiltration into the site of leaflet attachment seemed to possibly be a precursor to atherosclerotic lesion formation and appeared as early as 4 weeks after starting Western diet. No apparent differences were found between Irf5 sufficient and Irf5 deficient mice at either two or four weeks on Western diet.
In a bone marrow chimera study, we examined the effects of Irf5 from bone marrow- and non-bone marrow-derived cells on the accumulation of macrophages on aortic leaflets and in the tunica intima in the gld.apoE-/- mouse model of lupus and atherosclerosis. Macrophage accumulation did not correlate with differences in Irf5 production. However, the finding of macrophage accumulation on aortic leaflets suggests a role of macrophages in Libman-Sacks endocarditis, an inflammatory disease of the mitral and aortic valves seen in patients with lupus.
Together, our results do not support a role of Irf5 in macrophage infiltration into the aortic root. However, it is still likely that macrophages play a role in the pathogenesis of atherosclerotic lesion formation in a lupus mouse model, and it is an area of study worth exploring.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/16991 |
| Date | 18 June 2016 |
| Creators | Lok, Ling Ling |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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