title: Tumor necrosis factor alpha, citrullination, and peptidylarginine deiminase 4 in lung and joint inflammation.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Mandar
authors.initials: M
authors.lastname: Bawadekar
authors.affiliation: Research Animal Resource Center Comparative Pathology Lab and Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Gendron-Fitzpatrick
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Rebernick
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Daeun
authors.initials: D
authors.lastname: Shim
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Warner
authors.affiliation: Department of Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham and Birmingham VA Medical Center, Birmingham, AL, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Nicholas
authors.affiliation: Department of Medicine, The University of Vermont, Burlington, VT, USA.
authors.forename: Lennart K A
authors.initials: LK
authors.lastname: Lundblad
authors.affiliation: Departments of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.affiliation: Department of Medicine, University of Wisconsin-Madison and William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. mshelef@medicine.wisc.edu.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Shelef
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002956:Citrulline; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D000080002:Protein-Arginine Deiminase Type 4; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D002956:Citrulline; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse
keywords: Citrullination; Experimental arthritis; Lung; Peptidylarginine deiminase 4; Rheumatoid arthritis; TNF-α