Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism

Gustaf Wigerblad, Duygu B. Bas, Cátia Fernades-Cerqueira, Akilan Krishnamurthy, Kutty Selva Nandakumar, Katarzyna Rogoz, Jungo Kato, Katalin Sandor, Jie Su, Juan Miguel Jimenez-Andrade, Anja Finn, Alex Bersellini Farinotti, Khaled Amara, Karin Lundberg, Rikard Holmdahl, Per Johan Jakobsson, Vivianne Malmström, Anca I. Catrina, Lars Klareskog, Camilla I. Svensson

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Objective: An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation. Methods: Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin. Results: Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin. Conclusions: The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.

Original languageEnglish
Pages (from-to)730-7398
Number of pages6669
JournalAnnals of the Rheumatic Diseases
Volume75
Issue number4
DOIs
Publication statusPublished - 2016 Apr 1
Externally publishedYes

Fingerprint

Arthralgia
Chemokines
Autoantibodies
Inflammation
Pain
Osteoclasts
Rheumatoid Arthritis
Interleukin-8
Chemokine CXCL1
Proteins
Immunoglobulin G
Interleukin-8 Receptors
Chemical activation
Antibodies
Pathology
Neurons
Anti-Inflammatory Agents
Tissue
Sensory Receptor Cells
Chronic Pain

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wigerblad, G., Bas, D. B., Fernades-Cerqueira, C., Krishnamurthy, A., Nandakumar, K. S., Rogoz, K., ... Svensson, C. I. (2016). Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Annals of the Rheumatic Diseases, 75(4), 730-7398. https://doi.org/10.1136/annrheumdis-2015-208094

Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. / Wigerblad, Gustaf; Bas, Duygu B.; Fernades-Cerqueira, Cátia; Krishnamurthy, Akilan; Nandakumar, Kutty Selva; Rogoz, Katarzyna; Kato, Jungo; Sandor, Katalin; Su, Jie; Jimenez-Andrade, Juan Miguel; Finn, Anja; Farinotti, Alex Bersellini; Amara, Khaled; Lundberg, Karin; Holmdahl, Rikard; Jakobsson, Per Johan; Malmström, Vivianne; Catrina, Anca I.; Klareskog, Lars; Svensson, Camilla I.

In: Annals of the Rheumatic Diseases, Vol. 75, No. 4, 01.04.2016, p. 730-7398.

Research output: Contribution to journalArticle

Wigerblad, G, Bas, DB, Fernades-Cerqueira, C, Krishnamurthy, A, Nandakumar, KS, Rogoz, K, Kato, J, Sandor, K, Su, J, Jimenez-Andrade, JM, Finn, A, Farinotti, AB, Amara, K, Lundberg, K, Holmdahl, R, Jakobsson, PJ, Malmström, V, Catrina, AI, Klareskog, L & Svensson, CI 2016, 'Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism', Annals of the Rheumatic Diseases, vol. 75, no. 4, pp. 730-7398. https://doi.org/10.1136/annrheumdis-2015-208094
Wigerblad, Gustaf ; Bas, Duygu B. ; Fernades-Cerqueira, Cátia ; Krishnamurthy, Akilan ; Nandakumar, Kutty Selva ; Rogoz, Katarzyna ; Kato, Jungo ; Sandor, Katalin ; Su, Jie ; Jimenez-Andrade, Juan Miguel ; Finn, Anja ; Farinotti, Alex Bersellini ; Amara, Khaled ; Lundberg, Karin ; Holmdahl, Rikard ; Jakobsson, Per Johan ; Malmström, Vivianne ; Catrina, Anca I. ; Klareskog, Lars ; Svensson, Camilla I. / Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. In: Annals of the Rheumatic Diseases. 2016 ; Vol. 75, No. 4. pp. 730-7398.
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abstract = "Objective: An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation. Methods: Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin. Results: Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin. Conclusions: The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.",
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T1 - Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism

AU - Wigerblad, Gustaf

AU - Bas, Duygu B.

AU - Fernades-Cerqueira, Cátia

AU - Krishnamurthy, Akilan

AU - Nandakumar, Kutty Selva

AU - Rogoz, Katarzyna

AU - Kato, Jungo

AU - Sandor, Katalin

AU - Su, Jie

AU - Jimenez-Andrade, Juan Miguel

AU - Finn, Anja

AU - Farinotti, Alex Bersellini

AU - Amara, Khaled

AU - Lundberg, Karin

AU - Holmdahl, Rikard

AU - Jakobsson, Per Johan

AU - Malmström, Vivianne

AU - Catrina, Anca I.

AU - Klareskog, Lars

AU - Svensson, Camilla I.

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N2 - Objective: An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation. Methods: Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin. Results: Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin. Conclusions: The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.

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