PAD4 is Not Essential for Disease in the K/BxN Murine Autoantibody-mediated Model of Arthritis

Overview

Journal Arthritis Res Ther

Publisher Biomed Central

Specialty Rheumatology

Date 2012 May 4

PMID 22551352

Citations 43

Authors

Amanda S Rohrbach

Saskia Hemmers

Sanja Arandjelovic

Maripat Corr

Kerri A Mowen

Affiliations

Soon will be listed here.

Abstract

Introduction: Both murine and human genome-wide association studies have implicated peptidyl arginine deiminase (PAD4) as a susceptibility gene in rheumatoid arthritis (RA). In addition, patients with RA commonly have autoantibodies which recognize PAD4 or and/or citrullinated peptides. This study aims to evaluate the role of PAD4 in the effector phase of arthritis.

Methods: PAD4 knock out (KO) and wild type (WT) C57BL/6J mice were injected with K/BxN sera to induce disease. Progression of disease was monitored by measuring paw and ankle swelling and clinical indexes of disease, and pathogenesis was assessed by indexing of clinical progression on paws collected from WT and PAD4 KO mice injected with K/BxN serum. PAD4 activity was determined by visualization of neutrophil extracellular traps (NETs) and immunohistological analysis of histone citrullination.

Results: PAD4 activity is readily detectable in the inflamed synovium of WT but not PAD4 deficient animals, as demonstrated by histone citrullination and NET formation. However, PAD4 WT and KO animals develop K/BxN serum transfer disease with comparable severity and kinetics, with no statistically significant differences noted in clinical scores, swelling, joint erosion or joint invasion.

Conclusions: PAD4 WT and KO mice develop disease in the K/BxN serum transfer model of arthritis with similar severity and kinetics, indicating that PAD4 is dispensable in this effector phase model of disease.

Citing Articles

Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.

Englert H, Rangaswamy C, Kullik G, Divivier M, Gobel J, Hermans-Borgmeyer I FASEB J. 2025; 39(1):e70301.

PMID: 39777764 PMC: 11707982. DOI: 10.1096/fj.202402514R.

Recognition and control of neutrophil extracellular trap formation by MICL.

Malamud M, Whitehead L, McIntosh A, Colella F, Roelofs A, Kusakabe T Nature. 2024; 633(8029):442-450.

PMID: 39143217 PMC: 11390483. DOI: 10.1038/s41586-024-07820-3.

Neutrophil Extracellular Traps (NETs) and Atherosclerosis: Does Hypolipidemic Treatment Have an Effect?.

Adamidis P, Pantazi D, Moschonas I, Liberopoulos E, Tselepis A J Cardiovasc Dev Dis. 2024; 11(3).

PMID: 38535096 PMC: 10971437. DOI: 10.3390/jcdd11030072.

Role of inter-alpha-trypsin inhibitor heavy chain 4 and its citrullinated form in experimental arthritis murine models.

Iwai T, Ohyama A, Osada A, Nishiyama T, Shimizu M, Miki H Clin Exp Immunol. 2024; 215(3):302-312.

PMID: 38190323 PMC: 10876112. DOI: 10.1093/cei/uxae001.

The role of protein arginine deiminase 4-dependent neutrophil extracellular traps formation in ulcerative colitis.

Wang P, Liu D, Zhou Z, Liu F, Shen Y, You Q Front Immunol. 2023; 14:1144976.

PMID: 37143672 PMC: 10151647. DOI: 10.3389/fimmu.2023.1144976.

References

Jacobs J, Ortiz-Lopez A, Campbell J, Gerard C, Mathis D, Benoist C . Deficiency of CXCR2, but not other chemokine receptors, attenuates autoantibody-mediated arthritis in a murine model. Arthritis Rheum. 2010; 62(7):1921-32. PMC: 2994550. DOI: 10.1002/art.27470. View

Halvorsen E, Haavardsholm E, Pollmann S, Boonen A, van der Heijde D, Kvien T . Serum IgG antibodies to peptidylarginine deiminase 4 predict radiographic progression in patients with rheumatoid arthritis treated with tumour necrosis factor-alpha blocking agents. Ann Rheum Dis. 2008; 68(2):249-52. DOI: 10.1136/ard.2008.094490. View

Villanueva E, Yalavarthi S, Berthier C, Hodgin J, Khandpur R, Lin A . Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. 2011; 187(1):538-52. PMC: 3119769. DOI: 10.4049/jimmunol.1100450. View

Nakayama-Hamada M, Suzuki A, Kubota K, Takazawa T, Ohsaka M, Kawaida R . Comparison of enzymatic properties between hPADI2 and hPADI4. Biochem Biophys Res Commun. 2005; 327(1):192-200. DOI: 10.1016/j.bbrc.2004.11.152. View

Abdollahi-Roodsaz S, Joosten L, Roelofs M, Radstake T, Matera G, Popa C . Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum. 2007; 56(9):2957-67. DOI: 10.1002/art.22848. View

Lee E, Kang S, Paik D, Kim J, Youn J . Essential roles of Toll-like receptor-4 signaling in arthritis induced by type II collagen antibody and LPS. Int Immunol. 2005; 17(3):325-33. DOI: 10.1093/intimm/dxh212. View

Lee D, Friend D, Gurish M, Benoist C, Mathis D, Brenner M . Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science. 2002; 297(5587):1689-92. DOI: 10.1126/science.1073176. 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

Fuchs T, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers Jr D . Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010; 107(36):15880-5. PMC: 2936604. DOI: 10.1073/pnas.1005743107. View

10.

Li P, Li M, Lindberg M, Kennett M, Xiong N, Wang Y . PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med. 2010; 207(9):1853-62. PMC: 2931169. DOI: 10.1084/jem.20100239. View

11.

Borregaard N . Neutrophils, from marrow to microbes. Immunity. 2010; 33(5):657-70. DOI: 10.1016/j.immuni.2010.11.011. View

12.

Manzenreiter R, Kienberger F, Marcos V, Schilcher K, Krautgartner W, Obermayer A . Ultrastructural characterization of cystic fibrosis sputum using atomic force and scanning electron microscopy. J Cyst Fibros. 2011; 11(2):84-92. DOI: 10.1016/j.jcf.2011.09.008. View

13.

Stahl E, Raychaudhuri S, Remmers E, Xie G, Eyre S, Thomson B . Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010; 42(6):508-14. PMC: 4243840. DOI: 10.1038/ng.582. View

14.

Knuckley B, Causey C, Jones J, Bhatia M, Dreyton C, Osborne T . Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3. Biochemistry. 2010; 49(23):4852-63. PMC: 2884139. DOI: 10.1021/bi100363t. View

15.

Neeli I, Khan S, Radic M . Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol. 2008; 180(3):1895-902. DOI: 10.4049/jimmunol.180.3.1895. View

16.

Brinkmann V, Zychlinsky A . Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007; 5(8):577-82. DOI: 10.1038/nrmicro1710. View

17.

Wang J, Fathman J, Lugo-Villarino G, Scimone L, von Andrian U, Dorfman D . Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. J Clin Invest. 2006; 116(2):414-21. PMC: 1326147. DOI: 10.1172/JCI26631. View

18.

Klareskog L, Ronnelid J, Lundberg K, Padyukov L, Alfredsson L . Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol. 2008; 26:651-75. DOI: 10.1146/annurev.immunol.26.021607.090244. View

19.

Ji H, Ohmura K, Mahmood U, Lee D, Hofhuis F, Boackle S . Arthritis critically dependent on innate immune system players. Immunity. 2002; 16(2):157-68. DOI: 10.1016/s1074-7613(02)00275-3. View

20.

Hakkim A, Furnrohr B, Amann K, Laube B, Abu Abed U, Brinkmann V . Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A. 2010; 107(21):9813-8. PMC: 2906830. DOI: 10.1073/pnas.0909927107. View