Abstract
Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a glucose-6-phosphate isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice. Arthritis severity, serum anti-GPI antibody titers, and IL-6 concentrations were significantly reduced in Padi4 KO mice. The frequency of Th17 cells was decreased in GPI-immunized Padi4 KO mice, whereas WT and Padi4-deficient naïve CD4+ T cells displayed the same efficiencies for Th17 cell differentiation in vitro. In addition, the numbers of myeloid lineage cells were reduced with the increased expression of pro-apoptotic genes in GPI-immunized Padi4 KO mice. Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro. Our results suggest that PADI4 exacerbates arthritis with diverse immunological modifications.
Highlights
Rheumatoid arthritis (RA) is characterized by sustained and destructive polyarthritis with an autoimmune background
Padi4-deficient CD4+ T cells as well as WT CD4+ T cells efficiently differentiated into Th17 cells in vitro (Fig. 4D). These results suggested that the decreases observed in Th17 cells in Padi[4] KO glucose-6-phosphate isomerase (rhGPI)-induced arthritis (GIA) mice were due to some extrinsic causes during the course of the Recombinant human glucose-6-phosphate isomerase (rhGPI) immunization rather than to intrinsic defects in Padi4-deficient CD4+ T cells
We investigated the expression of IL-6 in the spleen in the pre-arthritic phase, a significant decrease was not observed in Peptidylarginine deiminase type 4 (PADI4) KO mice (Fig. 5B)
Summary
Rheumatoid arthritis (RA) is characterized by sustained and destructive polyarthritis with an autoimmune background. The RA-susceptible PADI4 haplotype has been shown to give rise to more stable PADI4 mRNA and is associated with increases in PAD4 protein levels[4]. These findings suggest that the enhanced and uncontrolled production of citrullinated antigens results in the development of an anti-citrullinated peptide antibody (ACPA) and the occurrence of joint inflammation in patients www.nature.com/scientificreports/. Two recent reports demonstrated that PADI4 is associated with ACPA-negative RA patients in Asian populations and one of the risk factors for bone destruction independent of ACPA status[9,10] These findings suggest an ACPA-independent pathway for the association of PADI4 with the pathogenesis of RA. Padi[4] exacerbated RA with diverse immunological modifications
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