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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

Th17 cell differentiation in Padi4 KO mice after the GPI immunization.(A,B) Proportions of Th1 and Th17 cells in the total amount of CD4+ T cells from inguinal lymph nodes 7 and 14 days after the immunization. Seven days after the immunization (WT n = 9, Padi4 KO n = 11), 14 days after the immunization (WT n = 6, Padi4 KO n = 6). (C) The CFSE dilution of CD4+ T cells from GPI-immunized inguinal lymph nodes was measured in response to an ex vivo stimulation with GPI (WT n = 3, Padi4 KO n = 3). (D) Proportion of in vitro differentiated Th17 cells in CD4+ T cells under Th17-polarizing conditions (WT n = 3, Padi4 KO n = 3). *p < 0.05, ***p < 0.001.
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f4: Th17 cell differentiation in Padi4 KO mice after the GPI immunization.(A,B) Proportions of Th1 and Th17 cells in the total amount of CD4+ T cells from inguinal lymph nodes 7 and 14 days after the immunization. Seven days after the immunization (WT n = 9, Padi4 KO n = 11), 14 days after the immunization (WT n = 6, Padi4 KO n = 6). (C) The CFSE dilution of CD4+ T cells from GPI-immunized inguinal lymph nodes was measured in response to an ex vivo stimulation with GPI (WT n = 3, Padi4 KO n = 3). (D) Proportion of in vitro differentiated Th17 cells in CD4+ T cells under Th17-polarizing conditions (WT n = 3, Padi4 KO n = 3). *p < 0.05, ***p < 0.001.

Mentions: CD4+ T cells, especially Th17 cells, play a pivotal role in the development of GIA21. In non-immunized DBA1 mice and GIA mice, the numbers of CD3+ T cells, CD62L− CD44+ CD4+ memory T cells, and CD62L− CD69+ CD4+ activated T cells in the spleens and iLNs were similar between Padi4 KO and WT mice (Fig. 3A–C), as was the number of CD25+ Foxp3+ CD4+ regulatory T cells (Fig. 3D). However, the frequency of iLN GPI-specific Th17 cells, but not Th1 cells, was significantly reduced in Padi4 KO mice either 7 or 14 days after the rhGPI immunization (Fig. 4A,B). On the other hand, no significant change was noted in the proliferation of CD4+ T cells, as analyzed by CFSE dilution, between WT and Padi4 KO mice (Fig. 4C).


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)

Th17 cell differentiation in Padi4 KO mice after the GPI immunization.(A,B) Proportions of Th1 and Th17 cells in the total amount of CD4+ T cells from inguinal lymph nodes 7 and 14 days after the immunization. Seven days after the immunization (WT n = 9, Padi4 KO n = 11), 14 days after the immunization (WT n = 6, Padi4 KO n = 6). (C) The CFSE dilution of CD4+ T cells from GPI-immunized inguinal lymph nodes was measured in response to an ex vivo stimulation with GPI (WT n = 3, Padi4 KO n = 3). (D) Proportion of in vitro differentiated Th17 cells in CD4+ T cells under Th17-polarizing conditions (WT n = 3, Padi4 KO n = 3). *p < 0.05, ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Th17 cell differentiation in Padi4 KO mice after the GPI immunization.(A,B) Proportions of Th1 and Th17 cells in the total amount of CD4+ T cells from inguinal lymph nodes 7 and 14 days after the immunization. Seven days after the immunization (WT n = 9, Padi4 KO n = 11), 14 days after the immunization (WT n = 6, Padi4 KO n = 6). (C) The CFSE dilution of CD4+ T cells from GPI-immunized inguinal lymph nodes was measured in response to an ex vivo stimulation with GPI (WT n = 3, Padi4 KO n = 3). (D) Proportion of in vitro differentiated Th17 cells in CD4+ T cells under Th17-polarizing conditions (WT n = 3, Padi4 KO n = 3). *p < 0.05, ***p < 0.001.
Mentions: CD4+ T cells, especially Th17 cells, play a pivotal role in the development of GIA21. In non-immunized DBA1 mice and GIA mice, the numbers of CD3+ T cells, CD62L− CD44+ CD4+ memory T cells, and CD62L− CD69+ CD4+ activated T cells in the spleens and iLNs were similar between Padi4 KO and WT mice (Fig. 3A–C), as was the number of CD25+ Foxp3+ CD4+ regulatory T cells (Fig. 3D). However, the frequency of iLN GPI-specific Th17 cells, but not Th1 cells, was significantly reduced in Padi4 KO mice either 7 or 14 days after the rhGPI immunization (Fig. 4A,B). On the other hand, no significant change was noted in the proliferation of CD4+ T cells, as analyzed by CFSE dilution, between WT and Padi4 KO mice (Fig. 4C).

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