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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Research article

Tumor necrosis factor alpha, citrullination, and peptidylarginine deiminase 4 in lung and joint inflammation

Authors: Mandar Bawadekar, Annette Gendron-Fitzpatrick, Ryan Rebernick, Daeun Shim, Thomas F. Warner, Anthony P. Nicholas, Lennart K. A. Lundblad, Paul R. Thompson, Miriam A. Shelef

Published in: Arthritis Research & Therapy | Issue 1/2016

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Abstract

Background

The relationship between lung and joint inflammation in rheumatoid arthritis is poorly understood. Lung inflammation with resultant protein citrullination may trigger anti-citrullinated protein antibodies, inflammation, and arthritis. Alternatively, lung and joint inflammation may be two manifestations of a single underlying pathology. The lung has increased citrullination and TNF-α levels are high in rheumatoid arthritis; however, it is unknown if TNF-α can induce lung protein citrullination. The citrullinating enzyme peptidylarginine deiminase 4 (PAD4) exacerbates TNF-α-induced arthritis, but a role for PAD4 in lung citrullination and TNF-α-induced lung inflammation has not been explored. Our aim was to use TNF-α-overexpressing mice to clarify the intersection of TNF-α, citrullination, PAD4, arthritis, and lung inflammation.

Methods

Lung protein citrullination in wild-type mice, mice that overexpress TNF-α systemically (TNF+), TNF+PAD4+/+, and TNF+PAD4-/- mice was quantified by both gel electrophoresis using a citrulline probe and western blot. Hematoxylin and eosin (H&E)-stained lung sections from TNF+PAD4+/+ and TNF+PAD4-/- mice were scored for lung inflammation. H&E-stained ankle joint sections from mice that overexpress TNF-α only in the lungs were assessed for arthritis.

Results

TNF+ mice have increased lung protein citrullination. TNF+PAD4-/- mice do not have significantly reduced lung protein citrullination, but do have decreased lung inflammation compared to TNF+PAD4+/+ mice. Mice that overexpress TNF-α only in the lungs do not develop arthritis.

Conclusions

PAD4 exacerbates lung inflammation downstream of TNF-α without having a major role in generalized protein citrullination in inflamed lungs. Also, TNF-α-induced lung inflammation is not sufficient to drive murine arthritis.
Appendix
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Metadata
Title
Tumor necrosis factor alpha, citrullination, and peptidylarginine deiminase 4 in lung and joint inflammation
Authors
Mandar Bawadekar
Annette Gendron-Fitzpatrick
Ryan Rebernick
Daeun Shim
Thomas F. Warner
Anthony P. Nicholas
Lennart K. A. Lundblad
Paul R. Thompson
Miriam A. Shelef
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-1068-0

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