Rheumatoid Arthritis increases sympathetic nervous system driven hematopoietic stem cell moblisation and atherogenisis

Al-Sharea A1,2*, Whillas A1,2 , Dragolevic D1,2, Hamilton J3, Muprhy AJ1,2

1 Baker IDI Heart and Diabetes Institute, Melbourne, 3004; 2 Central Clinical School, Monash University, Melbourne, 3800; 3 Walter and Eliza Hall Institute, Parkville, 3052

Background: The sympathetic arm of the autonomic nervous system plays an important role in the production and retention/release of hematopoietic stem and progenitor cells (HSPCs). -blockers have been suggested as potential therapy for various cardiovascular complications related to over-production of HSPCs. It has been shown that rheumatoid arthritis (RA) patients have elevated sympathetic activity. These patients also have an increased risk of cardiovascular disease (CVD), independent of traditional risk factors.

Aims: To investigate the role of sympathetic nervous system (SNS) overactivity in a model of RA and atherosclerosis. 

Results: Administration of the KBxN serum to 8 week old C57/B6 mice elicited clinical symptoms of RA (swelling of joints). Analysis of the blood using flow cytometry identified highly elevated levels of HSPC and myeloid (monocyte/neutrophil) populations. Further investigation of the bone marrow (BM) revealed an expansion of the HSPC pool. There was a strong skewing towards myeloid progenitors in the BM, explaining the elevation in blood myeloid populations. Staining of the BM shows an increase in markers of sympathetic activity, as identified by tyrosine hydroxylase staining. Treatment of arthritic mice with propanolol (1/2 receptor antagonist) and SR59230A (3 receptor antagonist) lead to a reduction in blood HSPC and myeloid populations.  To explore the role of RA in atherogenisis we fed LDLR-/- mice a high fat/high cholesterol diet for 14 weeks to stimulate lesion development. Mice were then switched to a normal chow diet for 3 weeks to allow lesion regression. A group of mice were injected with KBxN alone and KBxN with -blockers. Mice with RA displayed impaired lesion regression. Treatment with -blockers reduced this impairment. This was likely due to the reduction in HSPC mobilisation to the blood and myeloid expansion. 

Conclusion: Sympathetic overdrive in RA is partially responsible for the disordered hematopoietic state in the body. This leads to myeloid expansion especially in the monocyte subset, which has been shown to be directly linked to atherogenisis.

04 - RHEUMATOID ARTHRITIS INCREASES SYMPATHETIC NERVOUS SYSTEM DRIVEN HEMATOPOIETIC STEM CELL MOBILIZATION AND ATHEROGENESIS