Abstract
ObjectivesRheumatoid arthritis (RA), an inflammatory joint disorder, independently increases the risk of cardiovascular disease (CVD). IL‐1β contributes to both RA and CVD. We hypothesised that inhibiting IL‐1 signalling with the IL‐1R antagonist, anakinra, would dampen inflammation and promote resolution of atherosclerosis in arthritic mice.MethodsLow‐density lipoprotein receptor (Ldlr)‐deficient mice were fed a Western‐type diet for 14 weeks to develop atherosclerotic plaques. Mice were then switched to a chow diet, promoting lesion regression, and randomised to a control group or into groups where arthritis was induced by passive transfer of K/BxN arthritogenic serum. The arthritic mice were further randomised to vehicle or anakinra.ResultsArthritis impaired atherosclerotic lesion regression when cholesterol was lowered. This was associated with a higher burden of plaque macrophages, likely due to monocytosis, driven by myelopoiesis in the bone marrow and spleen. Interestingly, delayed intervention with anakinra had no effect on arthritis in these mice. However, a significant improvement in atherosclerotic plaque remodelling to a more stable phenotype was observed. This was associated with fewer circulating monocytes, caused by a reduction in splenic extramedullary myelopoiesis.ConclusionWe show that inhibiting IL‐1 signalling in arthritic mice with pre‐existing atherosclerosis promotes lesion remodelling to a more stable phenotype, that is less likely to rupture and cause ischemic events such as myocardial infarction. This suggests that IL‐1R antagonism may suppress CVD complications in patients with RA. Furthermore, inhibiting IL‐1β signalling in other patients with inflammatory diseases that also predispose to CVD may also benefit from anti‐IL‐1 therapy.
Highlights
IntroductionPatients with rheumatoid arthritis (RA), a chronic and debilitating inflammatory joint disease, have a ~ 2-fold increased risk of atherosclerosis-related cardiovascular disease (CVD).[1,2,3] CVD is the leading cause of mortality in these individuals.[1,2] While the mechanism(s) that cause accelerated atherosclerosis in patients is unknown, it is becoming increasingly clear that it occurs independent of traditional CV risk factors and that systemic inflammation is likely to play a pivotal role.[2,4] We have previously shown that inflammatory arthritis enhances haematopoiesis and monocytosis, which directly contributes to worsened atherosclerosis in murine models of RA.[5]Interleukin (IL)-1b is an inflammatory cytokine that promotes inflammatory joint diseases, such as RA
We employed the K/ BxN serum-transfer model of inflammatory arthritis as this is driven by interleukin (IL)-1b signalling[16,17] and LdlrÀ/À mice on a C57BL/6 background are susceptible, as we have previously shown.[5]
To recapitulate the clinical setting, anakinra was not commenced until day 4, when joint inflammation is evident in the K/BxN model
Summary
Patients with rheumatoid arthritis (RA), a chronic and debilitating inflammatory joint disease, have a ~ 2-fold increased risk of atherosclerosis-related cardiovascular disease (CVD).[1,2,3] CVD is the leading cause of mortality in these individuals.[1,2] While the mechanism(s) that cause accelerated atherosclerosis in patients is unknown, it is becoming increasingly clear that it occurs independent of traditional CV risk factors and that systemic inflammation is likely to play a pivotal role.[2,4] We have previously shown that inflammatory arthritis enhances haematopoiesis and monocytosis, which directly contributes to worsened atherosclerosis in murine models of RA.[5]Interleukin (IL)-1b is an inflammatory cytokine that promotes inflammatory joint diseases, such as RA. Patients with rheumatoid arthritis (RA), a chronic and debilitating inflammatory joint disease, have a ~ 2-fold increased risk of atherosclerosis-related cardiovascular disease (CVD).[1,2,3] CVD is the leading cause of mortality in these individuals.[1,2] While the mechanism(s) that cause accelerated atherosclerosis in patients is unknown, it is becoming increasingly clear that it occurs independent of traditional CV risk factors and that systemic inflammation is likely to play a pivotal role.[2,4] We have previously shown that inflammatory arthritis enhances haematopoiesis and monocytosis, which directly contributes to worsened atherosclerosis in murine models of RA.[5]. The IL-1Ra is essential for immune homeostasis, as mice lacking IL-1Ra spontaneously develop destructive arthritis.[7] an imbalance between IL-1b and the IL1Ra predisposes to RA.[8] Analysis of synovial fluid and synovial membrane obtained from RA patients revealed increased IL-1b expression
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