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Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model.

Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K - Sci Rep (2015)

Bottom Line: 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.Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Comparative analyses of wild-type (WT) and Padi4 knock out (KO) mice of recombinant human Glucose-6-phosphate isomerase (rhGPI)-induced arthritis (GIA).(A) The incidence of GIA. (B) The mean severity of GIA graded by previously reported methods. (WT n = 11, Padi4 KO n = 13) (C,D) Representative arthritic joint sections and mean histological scores were graded by previously reported methods 14 days after the immunization. ¶: inflammatory cell infiltration, §: cartilage destruction, †: bone erosion. Gray bars; WT, open bars; Padi4 KO. (E,F) The numbers of splenocytes and inguinal lymph node cells were counted 0, 7, and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 7 days after the immunization (WT n = 9, Padi4 KO n = 9), 14 days after the immunization (WT n = 14, Padi4 KO n = 16). *p < 0.05.
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f1: Comparative analyses of wild-type (WT) and Padi4 knock out (KO) mice of recombinant human Glucose-6-phosphate isomerase (rhGPI)-induced arthritis (GIA).(A) The incidence of GIA. (B) The mean severity of GIA graded by previously reported methods. (WT n = 11, Padi4 KO n = 13) (C,D) Representative arthritic joint sections and mean histological scores were graded by previously reported methods 14 days after the immunization. ¶: inflammatory cell infiltration, §: cartilage destruction, †: bone erosion. Gray bars; WT, open bars; Padi4 KO. (E,F) The numbers of splenocytes and inguinal lymph node cells were counted 0, 7, and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 7 days after the immunization (WT n = 9, Padi4 KO n = 9), 14 days after the immunization (WT n = 14, Padi4 KO n = 16). *p < 0.05.

Mentions: WT and Padi4 KO mice both developed arthritis approximately 7 days after the rhGPI immunization and arthritis scores increased between 8 and 14 days after the immunization. Most of the immunized WT and Padi4 KO mice developed arthritis, and no significant difference was observed in the incidence of arthritis (Fig. 1A). Arthritis severity scores were significantly lower in Padi4 KO mice than in WT mice (Fig. 1B). The histological scores for inflamed joints were also lower in Padi4 KO mice than in WT mice (Fig. 1C,D). These results demonstrated that Padi4 was associated with the exacerbation of GIA.


Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model.

Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K - Sci Rep (2015)

Comparative analyses of wild-type (WT) and Padi4 knock out (KO) mice of recombinant human Glucose-6-phosphate isomerase (rhGPI)-induced arthritis (GIA).(A) The incidence of GIA. (B) The mean severity of GIA graded by previously reported methods. (WT n = 11, Padi4 KO n = 13) (C,D) Representative arthritic joint sections and mean histological scores were graded by previously reported methods 14 days after the immunization. ¶: inflammatory cell infiltration, §: cartilage destruction, †: bone erosion. Gray bars; WT, open bars; Padi4 KO. (E,F) The numbers of splenocytes and inguinal lymph node cells were counted 0, 7, and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 7 days after the immunization (WT n = 9, Padi4 KO n = 9), 14 days after the immunization (WT n = 14, Padi4 KO n = 16). *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544002&req=5

f1: Comparative analyses of wild-type (WT) and Padi4 knock out (KO) mice of recombinant human Glucose-6-phosphate isomerase (rhGPI)-induced arthritis (GIA).(A) The incidence of GIA. (B) The mean severity of GIA graded by previously reported methods. (WT n = 11, Padi4 KO n = 13) (C,D) Representative arthritic joint sections and mean histological scores were graded by previously reported methods 14 days after the immunization. ¶: inflammatory cell infiltration, §: cartilage destruction, †: bone erosion. Gray bars; WT, open bars; Padi4 KO. (E,F) The numbers of splenocytes and inguinal lymph node cells were counted 0, 7, and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 7 days after the immunization (WT n = 9, Padi4 KO n = 9), 14 days after the immunization (WT n = 14, Padi4 KO n = 16). *p < 0.05.
Mentions: WT and Padi4 KO mice both developed arthritis approximately 7 days after the rhGPI immunization and arthritis scores increased between 8 and 14 days after the immunization. Most of the immunized WT and Padi4 KO mice developed arthritis, and no significant difference was observed in the incidence of arthritis (Fig. 1A). Arthritis severity scores were significantly lower in Padi4 KO mice than in WT mice (Fig. 1B). The histological scores for inflamed joints were also lower in Padi4 KO mice than in WT mice (Fig. 1C,D). These results demonstrated that Padi4 was associated with the exacerbation of GIA.

Bottom Line: 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.Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

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.

No MeSH data available.


Related in: MedlinePlus