Autocitrullination Confers Monocyte Chemotactic Properties to Peptidylarginine Deiminase 4

Overview

Journal Sci Rep

Specialty Science

Date 2023 May 10

PMID 37160933

Authors

Ken Yoshida

Haruyasu Ito

Daisaburo Kurosaka

Ryo Ikeda

Kentaro Noda

Mitsuru Saito

Daitaro Kurosaka

Affiliations

Soon will be listed here.

Abstract

Peptidylarginine deiminase 4 (PAD4) contributes to the production of citrullinated proteins as autoantigens for anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA). PAD4 can also self-deiminate via autocitrullination. However, the role of this process in RA pathogenesis has not been elucidated. This study aimed to clarify PAD4 function before and after autocitrullination and identify citrullinated PAD4 in the synovial fluid of patients with RA. The autocitrullination of recombinant human PAD4 (rhPAD4) was catalyzed in vitro and determined using anti-modified citrulline immunoblotting. Monocyte chemotaxis was evaluated using Boyden chambers, and citrullinated rhPAD4's ability to induce arthritis was assessed in a C57BL/6J mouse model. Citrullinated PAD4 levels were measured in the synovial fluid of patients with RA and osteoarthritis using a novel enzyme-linked immunosorbent assay. Chemotactic findings showed that citrullinated rhPAD4 recruited monocytes in vitro, whereas unmodified rhPAD4 did not. Compared to unmodified rhPAD4, citrullinated rhPAD4 induced greater inflammation in mouse joints through monocyte migration. More citrullinated PAD4 was found in the synovial fluid of patients with RA than in those with osteoarthritis. Citrullinated PAD4 was even detected in ACPA-negative patients with RA. The autocitrullination of PAD4 amplified inflammatory arthritis through monocyte recruitment, suggesting an ACPA-independent role of PAD4 in RA pathogenesis.

References

Suzuki A, Kochi Y, Shoda H, Seri Y, Fujio K, Sawada T . Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice. BMC Musculoskelet Disord. 2016; 17:205. PMC: 4858923. DOI: 10.1186/s12891-016-1055-2. View

Firestein G . Evolving concepts of rheumatoid arthritis. Nature. 2003; 423(6937):356-61. DOI: 10.1038/nature01661. View

Krishnamurthy A, Joshua V, Hensvold A, Jin T, Sun M, Vivar N . Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis. 2015; 75(4):721-9. PMC: 4819614. DOI: 10.1136/annrheumdis-2015-208093. View

Darrah E, Andrade F . Rheumatoid arthritis and citrullination. Curr Opin Rheumatol. 2017; 30(1):72-78. PMC: 5848217. DOI: 10.1097/BOR.0000000000000452. View

Sun M, Rethi B, Krishnamurthy A, Joshua V, Circiumaru A, Hensvold A . Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts. Ann Rheum Dis. 2019; 78(12):1621-1631. PMC: 6900251. DOI: 10.1136/annrheumdis-2018-214967. View

Sur Chowdhury C, Giaglis S, Walker U, Buser A, Hahn S, Hasler P . Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility. Arthritis Res Ther. 2014; 16(3):R122. PMC: 4229860. DOI: 10.1186/ar4579. View

Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Mechin M . Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum. 2007; 56(11):3541-53. DOI: 10.1002/art.22983. View

Bang S, Han T, Choi C, Sung Y, Bae S, Kang C . Peptidyl arginine deiminase type IV (PADI4) haplotypes interact with shared epitope regardless of anti-cyclic citrullinated peptide antibody or erosive joint status in rheumatoid arthritis: a case control study. Arthritis Res Ther. 2010; 12(3):R115. PMC: 2911908. DOI: 10.1186/ar3051. View

Kinloch A, Lundberg K, Wait R, Wegner N, Lim N, Zendman A . Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis. Arthritis Rheum. 2008; 58(8):2287-95. DOI: 10.1002/art.23618. View

10.

Curran A, Naik P, Giles J, Darrah E . PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets. Nat Rev Rheumatol. 2020; 16(6):301-315. DOI: 10.1038/s41584-020-0409-1. View

11.

Ruth J, Arendt M, Amin M, Ahmed S, Marotte H, Rabquer B . Expression and function of CXCL16 in a novel model of gout. Arthritis Rheum. 2010; 62(8):2536-44. PMC: 2921006. DOI: 10.1002/art.27518. View

12.

Terao C, Yamada R, Ohmura K, Takahashi M, Kawaguchi T, Kochi Y . The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population. Hum Mol Genet. 2011; 20(13):2680-5. DOI: 10.1093/hmg/ddr161. View

13.

Fan L, He D, Wang Q, Zong M, Zhang H, Yang L . Citrullinated vimentin stimulates proliferation, pro-inflammatory cytokine secretion, and PADI4 and RANKL expression of fibroblast-like synoviocytes in rheumatoid arthritis. Scand J Rheumatol. 2012; 41(5):354-8. DOI: 10.3109/03009742.2012.670263. View

14.

Wigerblad G, Bas D, Fernades-Cerqueira C, Krishnamurthy A, Nandakumar K, Rogoz K . Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann Rheum Dis. 2015; 75(4):730-8. PMC: 4819624. DOI: 10.1136/annrheumdis-2015-208094. View

15.

Yoshida K, Korchynskyi O, Tak P, Isozaki T, Ruth J, Campbell P . Citrullination of epithelial neutrophil-activating peptide 78/CXCL5 results in conversion from a non-monocyte-recruiting chemokine to a monocyte-recruiting chemokine. Arthritis Rheumatol. 2014; 66(10):2716-27. DOI: 10.1002/art.38750. View

16.

Naranbhai V, Fairfax B, Makino S, Humburg P, Wong D, Ng E . Genomic modulators of gene expression in human neutrophils. Nat Commun. 2015; 6:7545. PMC: 4507005. DOI: 10.1038/ncomms8545. View

17.

Yunna C, Mengru H, Lei W, Weidong C . Macrophage M1/M2 polarization. Eur J Pharmacol. 2020; 877:173090. DOI: 10.1016/j.ejphar.2020.173090. View

18.

Ruth J, Park C, Amin M, Lesch C, Marotte H, Shahrara S . Interleukin-18 as an in vivo mediator of monocyte recruitment in rodent models of rheumatoid arthritis. Arthritis Res Ther. 2010; 12(3):R118. PMC: 2911912. DOI: 10.1186/ar3055. View

19.

Andrade F, Darrah E, Gucek M, Cole R, Rosen A, Zhu X . Autocitrullination of human peptidyl arginine deiminase type 4 regulates protein citrullination during cell activation. Arthritis Rheum. 2010; 62(6):1630-40. PMC: 2951335. DOI: 10.1002/art.27439. View

20.

Mergaert A, Bawadekar M, Nguyen T, Massarenti L, Holmes C, Rebernick R . Reduced Anti-Histone Antibodies and Increased Risk of Rheumatoid Arthritis Associated with a Single Nucleotide Polymorphism in PADI4 in North Americans. Int J Mol Sci. 2019; 20(12). PMC: 6627847. DOI: 10.3390/ijms20123093. View