THU0076 Antibodies to citrullinated protein antigens (ACPAS) induce adipose tissue dysfunction impairing adipocyte differentiation, lipid accumulation and promoting macrophage polarisation. in vitro effect of biologic dmards
Authors: I. Arias De La Rosa, M. Ruiz-Ponce, P. Ruiz-Limón, Y. Jiménez-Gómez, C. Pérez-Sánchez, I. Cecchi, M.D.C. Ábalos-Aguilera, E. Collantes-Estévez, A. Escudero, C. López-Pedrera, N. Barbarroja
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Adipose tissue (AT) dysfunction is an important determinant of inflammation- or lipid-induced metabolic complications. Rheumatoid arthritis (RA) is closely associated with metabolic comorbidities such as obesity or insulin resistance (IR). ACPAs are involved in the development of cardiovascular disease associated to this disorder. However, the role of ACPAs on the adipose tissue (AT) function is unravelled. <h3>Objectives</h3> 1) To analyse the direct effects of ACPAs on the AT function: adipocyte differentiation, macrophage polarisation and lipid accumulation, and 2) To evaluate the effects tocilizumab (TCZ) or infliximab (IFX) on the metabolic alterations induced by ACPAs on AT. <h3>Methods</h3> IgGs-NHS (Normal Human Serum) and IgGs-ACPAs were isolated from serum of 20 controls and 20 RA patients. 3 T3-L1 fibroblast were treated with IgG-NHS or IgG-ACPAs alone or in combination with IFX or TCZ during several stages of the differentiation to adipocytes (day 0 and day 9). Lipid accumulation was analysed by oil red 0 (ORO) staining. M0 macrophages from THP-1 cells were treated with IgG-NHS or IgG-ACPAs alone for 12 hour or in combination with IFX and TCZ for another 12 hour. Macrophage polarisation was analysed by flow cytometry. Visceral and subcutaneous AT samples were obtained from 8 obese patients through bariatric surgery. AT samples were treated <i>ex vivo</i> with IgGs-NHS or IgG-ACPAs alone or in combination with biological DMARDs. Protein and gene expression of molecules involved in adipogenesis, inflammation, insulin signalling and lipid accumulation was analysed through RT-PCR, western blot and ELISA in all the experiments. <h3>Results</h3> <i>In vitro</i> treatment of M0 macrophages with IgG-ACPAs induced M1 polarisation state and impaired insulin signalling. 3 T3-L1 fibroblast treated with IgG-ACPAs at day 0 showed an impaired adipocyte differentiation shown by a reduction of genes involved in adipogenesis and lipid accumulation. Levels of accumulated lipids were also significantly reduced. Likewise, genes involved in insulin signalling were reduced. Treatment with IFX and TCZ after differentiation reverted the expression of these genes. At human adipose tissue level, the treatment with IgGs-ACPAs increased the levels of inflammatory markers, accompanied by a downregulation of genes involved in lipid accumulation, adipogenesis and insulin signalling. After treatment with biological DMARDs, inflammatory and metabolic alterations were reverted on human AT explants. <h3>Conclusions</h3> 1) ACPAs impairs AT function, acting in both, macrophages and adipocytes, inducing M1 macrophage polarisation and impairing adipogenesis and lipid accumulation in adipocytes, favouring an IR state. 2) TCZ and IFX might reverse the metabolic alterations induced in AT by ACPAs. 3) Targeting these autoantibodies would be an excellent therapeutic strategy to restore AT function and reduce the metabolic complications related to RA. <h3>Acknowledgements</h3> Funded by the Minister of Health (ISCIII, PI17/01316 and CP15/00158 and RIER RD16/0012/0015) cofinanced with FEDER funds. <h3>Disclosure of Interest</h3> None declared