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 language | English |
|---|---|
| Pages (from-to) | 730-7398 |
| Number of pages | 6669 |
| Journal | Annals of the Rheumatic Diseases |
| Volume | 75 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2016 Apr 1 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology and Allergy
- Rheumatology
- Immunology
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
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 journal › Article
}
TY - JOUR
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.
PY - 2016/4/1
Y1 - 2016/4/1
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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84961878456&partnerID=8YFLogxK
U2 - 10.1136/annrheumdis-2015-208094
DO - 10.1136/annrheumdis-2015-208094
M3 - Article
C2 - 26613766
AN - SCOPUS:84961878456
VL - 75
SP - 730
EP - 7398
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
SN - 0003-4967
IS - 4
ER -