Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients

Abstract

Citrullinated neoepitopes have emerged as key triggers of autoantibodies anti-citrullinated protein antibodies (ACPA) synthesis in rheumatoid arthritis (RA) patients. Apart from their critical role in homeostasis and thrombosis, platelets have a significant contribution to inflammation as well. Although anuclear in nature, platelets have an intricate post-translational modification machinery. Till now, citrullination in platelets and its contribution to trigger autoantibodies ACPA production in RA is an unexplored research direction. Herein, we investigated the expression of peptidylarginine deiminase (PAD) enzymes and citrullinated proteins/peptides in the human platelets and platelet derived microparticles (PDP). Both PAD4 mRNA and protein, but not the other PAD isoforms, are detectable in the human platelets. With a strict filtering criterion,108 citrullination sites present on 76 proteins were identified in the human platelets, and 55 citrullinated modifications present on 37 different proteins were detected in the PDPs. Among them, some are well-known citrullinated autoantigens associated with RA. Citrullinated forms of thrombospondin-1, β-actin, and platelet factor-4 (also known as CXCL4) are highly immunogenic and bound by autoantibodies ACPA. Furthermore, ACPA from RA sera and synovial fluids recognized citrullinated proteins from platelets and significantly activated them as evidenced by P-selectin upregulation and sCD40 L secretion. These results clearly demonstrate the presence of citrullinated autoantigens in platelets and PDPs, thus could serve as potential targets of ACPA in RA.

GnRH Induces Citrullination of the Cytoskeleton in Murine Gonadotrope Cells

“…Our results are consistent with previous work identifying citrullinated cytoskeletal filaments in various biological systems [ 10 , 27 , 46 , 47 ]; however, very few studies have examined the effects of citrullination on cytoskeletal dynamics. Work by Inagaki et al found that the calcium-dependent citrullination of the intermediate filament vimentin at the amino terminal head results in filament disassembly.…”

Modulation of plasmacytoid dendritic cells response in inflammation and autoimmunity

“…Consistent with these data, exogenous CXCL4 induced the production of IL‐17 from activated CD4 + T cells 135 . Increased expression of CXCL4 and increased reactivity to citrullinated forms of CXCL4 were found in synovial biopsies of patients with early RA 136 and in the sera of RA patients, respectively 137 . Citrullination is a key element that triggers the production of anti‐citrullinated protein autoantibodies (ACPA), a hallmark in RA 137 .…”

“…Increased expression of CXCL4 and increased reactivity to citrullinated forms of CXCL4 were found in synovial biopsies of patients with early RA 136 and in the sera of RA patients, respectively 137 . Citrullination is a key element that triggers the production of anti‐citrullinated protein autoantibodies (ACPA), a hallmark in RA 137 . So far, the implications of CXCL4 for disease in SLE, pSS, Pso, PsA, and RA have only been observational, and the mechanisms by which the chemokine plays a role in the pathogenesis of these diseases needs to be elucidated.…”

“…135 Increased expression of CXCL4 and increased reactivity to citrullinated forms of CXCL4 were found in synovial biopsies of patients with early RA 136 and in the sera of RA patients, respectively. 137 Citrullination is a key element that triggers the production of anti-citrullinated protein autoantibodies (ACPA), a hallmark in RA. 137 So far, the implications of CXCL4 for disease in F I G U R E 4 A subset of chemokines can act as nucleic acid (NA) delivery vectors that amplify toll-like receptor (TLR) signaling and enhance pro-inflammatory cytokine expression in immune cells.…”

“…137 Citrullination is a key element that triggers the production of anti-citrullinated protein autoantibodies (ACPA), a hallmark in RA. 137 So far, the implications of CXCL4 for disease in F I G U R E 4 A subset of chemokines can act as nucleic acid (NA) delivery vectors that amplify toll-like receptor (TLR) signaling and enhance pro-inflammatory cytokine expression in immune cells. SLE, pSS, Pso, PsA, and RA have only been observational, and the mechanisms by which the chemokine plays a role in the pathogenesis of these diseases needs to be elucidated.…”