Peptidylarginine deiminase 4 contributes to tumor necrosis factor α-induced inflammatory arthritis

Miriam A. Shelef, Jeremy Sokolove, Lauren J. Lahey, Catriona A. Wagner, Eric K. Sackmann, Thomas F. Warner, Yanming Wang, David J. Beebe, William H. Robinson, Anna Huttenlocher

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Objective Peptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme that has multiple associations with inflammation. In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed. ACPA immune complexes can deposit in the joint and induce the production of tumor necrosis factor α (TNFα), a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis. Further, in other settings, TNFα has been shown to induce PAD4 activity and modulate antibody formation. We undertook this study to investigate whether TNFα and PAD4 may synergistically exacerbate autoantibody production and inflammatory arthritis. Methods To determine whether TNFα and PAD4 augment autoantibody production and inflammatory arthritis, we first used a multiplex assay to determine whether mice with chronic inflammatory arthritis due to overexpression of TNFα develop autoantibodies against native and citrullinated antigens. With TNF+ PAD4+/+ and TNF +PAD4-/- mice, we then compared serum autoantibody levels by multiplex array, lymphocyte activation by flow cytometry, total serum IgG levels by enzyme-linked immunosorbent assay, arthritis by clinical and histologic scoring, and systemic inflammation using microfluidic devices. Results TNFα-overexpressing mice had increased levels of autoantibodies reactive against native and citrullinated antigens. PAD4-/- mice with TNFα-induced arthritis had lower levels of autoantibodies reactive against native and citrullinated antigens, decreased T cell activation and total IgG levels, and reduced inflammation and arthritis compared to PAD4 +/+ TNFα-overexpressing mice. Conclusion PAD4 mediates autoantibody production and inflammatory arthritis downstream of TNFα.

Original languageEnglish (US)
Pages (from-to)1482-1491
Number of pages10
JournalArthritis and Rheumatology
Volume66
Issue number6
DOIs
StatePublished - Jan 1 2014

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Arthritis
Tumor Necrosis Factor-alpha
Autoantibodies
Lab-On-A-Chip Devices
Inflammation
Antigens
Rheumatoid Arthritis
protein-arginine deiminase
Immunoglobulin G
Joints
CD27 Antigens
Proteins
Antibodies
Lymphocyte Activation
Antigen-Antibody Complex
Serum
Antibody Formation
Flow Cytometry
Enzyme-Linked Immunosorbent Assay
Cytokines

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Shelef, M. A., Sokolove, J., Lahey, L. J., Wagner, C. A., Sackmann, E. K., Warner, T. F., ... Huttenlocher, A. (2014). Peptidylarginine deiminase 4 contributes to tumor necrosis factor α-induced inflammatory arthritis. Arthritis and Rheumatology, 66(6), 1482-1491. https://doi.org/10.1002/art.38393
Shelef, Miriam A. ; Sokolove, Jeremy ; Lahey, Lauren J. ; Wagner, Catriona A. ; Sackmann, Eric K. ; Warner, Thomas F. ; Wang, Yanming ; Beebe, David J. ; Robinson, William H. ; Huttenlocher, Anna. / Peptidylarginine deiminase 4 contributes to tumor necrosis factor α-induced inflammatory arthritis. In: Arthritis and Rheumatology. 2014 ; Vol. 66, No. 6. pp. 1482-1491.
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abstract = "Objective Peptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme that has multiple associations with inflammation. In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed. ACPA immune complexes can deposit in the joint and induce the production of tumor necrosis factor α (TNFα), a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis. Further, in other settings, TNFα has been shown to induce PAD4 activity and modulate antibody formation. We undertook this study to investigate whether TNFα and PAD4 may synergistically exacerbate autoantibody production and inflammatory arthritis. Methods To determine whether TNFα and PAD4 augment autoantibody production and inflammatory arthritis, we first used a multiplex assay to determine whether mice with chronic inflammatory arthritis due to overexpression of TNFα develop autoantibodies against native and citrullinated antigens. With TNF+ PAD4+/+ and TNF +PAD4-/- mice, we then compared serum autoantibody levels by multiplex array, lymphocyte activation by flow cytometry, total serum IgG levels by enzyme-linked immunosorbent assay, arthritis by clinical and histologic scoring, and systemic inflammation using microfluidic devices. Results TNFα-overexpressing mice had increased levels of autoantibodies reactive against native and citrullinated antigens. PAD4-/- mice with TNFα-induced arthritis had lower levels of autoantibodies reactive against native and citrullinated antigens, decreased T cell activation and total IgG levels, and reduced inflammation and arthritis compared to PAD4 +/+ TNFα-overexpressing mice. Conclusion PAD4 mediates autoantibody production and inflammatory arthritis downstream of TNFα.",
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Shelef, MA, Sokolove, J, Lahey, LJ, Wagner, CA, Sackmann, EK, Warner, TF, Wang, Y, Beebe, DJ, Robinson, WH & Huttenlocher, A 2014, 'Peptidylarginine deiminase 4 contributes to tumor necrosis factor α-induced inflammatory arthritis', Arthritis and Rheumatology, vol. 66, no. 6, pp. 1482-1491. https://doi.org/10.1002/art.38393

Peptidylarginine deiminase 4 contributes to tumor necrosis factor α-induced inflammatory arthritis. / Shelef, Miriam A.; Sokolove, Jeremy; Lahey, Lauren J.; Wagner, Catriona A.; Sackmann, Eric K.; Warner, Thomas F.; Wang, Yanming; Beebe, David J.; Robinson, William H.; Huttenlocher, Anna.

In: Arthritis and Rheumatology, Vol. 66, No. 6, 01.01.2014, p. 1482-1491.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Peptidylarginine deiminase 4 contributes to tumor necrosis factor α-induced inflammatory arthritis

AU - Shelef, Miriam A.

AU - Sokolove, Jeremy

AU - Lahey, Lauren J.

AU - Wagner, Catriona A.

AU - Sackmann, Eric K.

AU - Warner, Thomas F.

AU - Wang, Yanming

AU - Beebe, David J.

AU - Robinson, William H.

AU - Huttenlocher, Anna

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Objective Peptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme that has multiple associations with inflammation. In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed. ACPA immune complexes can deposit in the joint and induce the production of tumor necrosis factor α (TNFα), a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis. Further, in other settings, TNFα has been shown to induce PAD4 activity and modulate antibody formation. We undertook this study to investigate whether TNFα and PAD4 may synergistically exacerbate autoantibody production and inflammatory arthritis. Methods To determine whether TNFα and PAD4 augment autoantibody production and inflammatory arthritis, we first used a multiplex assay to determine whether mice with chronic inflammatory arthritis due to overexpression of TNFα develop autoantibodies against native and citrullinated antigens. With TNF+ PAD4+/+ and TNF +PAD4-/- mice, we then compared serum autoantibody levels by multiplex array, lymphocyte activation by flow cytometry, total serum IgG levels by enzyme-linked immunosorbent assay, arthritis by clinical and histologic scoring, and systemic inflammation using microfluidic devices. Results TNFα-overexpressing mice had increased levels of autoantibodies reactive against native and citrullinated antigens. PAD4-/- mice with TNFα-induced arthritis had lower levels of autoantibodies reactive against native and citrullinated antigens, decreased T cell activation and total IgG levels, and reduced inflammation and arthritis compared to PAD4 +/+ TNFα-overexpressing mice. Conclusion PAD4 mediates autoantibody production and inflammatory arthritis downstream of TNFα.

AB - Objective Peptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme that has multiple associations with inflammation. In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed. ACPA immune complexes can deposit in the joint and induce the production of tumor necrosis factor α (TNFα), a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis. Further, in other settings, TNFα has been shown to induce PAD4 activity and modulate antibody formation. We undertook this study to investigate whether TNFα and PAD4 may synergistically exacerbate autoantibody production and inflammatory arthritis. Methods To determine whether TNFα and PAD4 augment autoantibody production and inflammatory arthritis, we first used a multiplex assay to determine whether mice with chronic inflammatory arthritis due to overexpression of TNFα develop autoantibodies against native and citrullinated antigens. With TNF+ PAD4+/+ and TNF +PAD4-/- mice, we then compared serum autoantibody levels by multiplex array, lymphocyte activation by flow cytometry, total serum IgG levels by enzyme-linked immunosorbent assay, arthritis by clinical and histologic scoring, and systemic inflammation using microfluidic devices. Results TNFα-overexpressing mice had increased levels of autoantibodies reactive against native and citrullinated antigens. PAD4-/- mice with TNFα-induced arthritis had lower levels of autoantibodies reactive against native and citrullinated antigens, decreased T cell activation and total IgG levels, and reduced inflammation and arthritis compared to PAD4 +/+ TNFα-overexpressing mice. Conclusion PAD4 mediates autoantibody production and inflammatory arthritis downstream of TNFα.

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Shelef MA, Sokolove J, Lahey LJ, Wagner CA, Sackmann EK, Warner TF et al. Peptidylarginine deiminase 4 contributes to tumor necrosis factor α-induced inflammatory arthritis. Arthritis and Rheumatology. 2014 Jan 1;66(6):1482-1491. https://doi.org/10.1002/art.38393