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

• 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

Keyword

Animals

Arthralgia/*immunology

Autoantibodies/*immunology/pharmacology

Behavior

Animal/drug effects

Case-Control Studies

Chemokine CXCL1/drug effects/*immunology

Chemokines

Citrulline/*immunology

Inflammation

Interleukin-8/drug effects/*immunology

Male

Mice

Mice

Inbred BALB C

Nociception/drug effects/*physiology

Osteoclasts/drug effects/*immunology

Receptors

Interleukin-8/antagonists & inhibitors

Sulfonamides/pharmacology

Ant-CCP

Autoantibodies

Fibromyalgis/Pain Syndromes

Rheumatoid Arthritis

Publication and Content Type

ref (subject category)

art (subject category)