Background: Several studies have shown that the anti-inflammatory/anti-oxidant properties of HDL are impaired in the inflammatory environment of rheumatic diseases, including rheumatoid arthritis (RA). HMG-CoA reductase inhibitors beside their role in decreasing cholesterol levels also display anti-inflammatory and immune-modulating properties both in vivo and in vitro . Nevertheless, the effects of statin use in RA patients are rather contradictory.

Objectives: In the present study, we aimed to assess the effect of established and novel HDL-targeting agents on HDL properties in the context of systemic inflammatory responses.

Methods: Screening of an FDA approved drug library for their potency in enhancing or restoring the structure and function of HDL in vitro highlighted that two substances, lovastatin and dantrolene could have a positive effect in regulating inflammation in RA. In this context, we used the collagen-induced arthritis (CIA) model in the DBA/1J mouse strain and we administrated lovastatin, dantrolene or their vehicle therapeutically to study their effect in disease progression. We also utilized the atherosclerosis-prone transgenic mouse model of spontaneous arthritis K/BxAg7 to investigate the effect of a common lipid-lowering drug (simvastatin) in arthritis progression and atherosclerosis development.

Results: We found that treatment with lovastatin worsened arthritis phenotype by reducing T regulatory cells (Tregs) in the draining lymph nodes and by increasing infiltration of myeloid cells in the spleen of CIA mice. On the contrary, dantrolene administration improved arthritis severity in the CIA model by reducing macrophage and dendritic cell infiltration of the spleen, and by blocking differentiation of naive CD4 ⁺ T cells into effector memory cells. Additionally, we found an increased paraoxonase and arylesterase activity of PON1 and an improved anti-oxidant capacity of HDL in the dantrolene-treated group, which was in line with our in vitro findings. Regarding the effect of simvastatin in the K/BxAg7 model, we found that inhibition of cholesterol biosynthesis blocked CD8 ⁺ T cell differentiation into effector memory cells and increased Tregs in the spleen. Additionally, simvastatin restored the anti-oxidant capacity of HDL in mice receiving atherogenic diet, although it had no beneficial impact on arthritis progression.

Conclusion: Altogether, even though blockade of cholesterol biosynthesis did not seem to have a clear role in arthritis severity in both mouse models of experimental arthritis herein, the administration of dantrolene moderated arthritis by altering key pathogenic cell subsets and improved PON1 activity in the CIA model.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.