Submitted April 8, 2008
Accepted August 30, 2008
CD44-specific antibody treatment and CD44 deficiency exert distinct effects on leukocyte recruitment in experimental arthritis
Gabor Hutas, Eva Bajnok, Istvan Gal, Alison Finnegan, Tibor T Glant, and Katalin Mikecz*
Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, United States
Section of Rheumatology, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
* Corresponding author; email: katalin_mikecz{at}rsh.net.
CD44, the leukocyte adhesion receptor for hyaluronan, has been considered as a therapeutic target on the basis of the robust anti-inflammatory effect of CD44-specific antibodies in animal models of immune-mediated diseases. However, CD44 deficiency does not provide substantial protection against inflammation. Using intravital video microscopy in a murine model of rheumatoid arthritis, here we show that CD44 deficiency and anti-CD44 antibody treatment exert disparate effects on leukocyte recruitment in inflamed joints. Leukocyte rolling, which is increased in CD44-deficient mice, is promptly abrogated in anti-CD44-treated wild type mice. CD44-specific antibodies also trigger platelet deposition on granulocytes and subsequent depletion of this leukocyte subset in the circulation. These in vivo effects require CD44 crosslinking, and are reproducible with an antibody against Gr-1, a molecule that, like CD44, is highly expressed on granulocytes. Anticoagulant pre-treatment, which prevents platelet deposition, mitigates both granulocyte depletion and the suppressive effect of CD44-specific antibody on joint swelling. Our observations suggest that crosslinking of prominent cell-surface molecules such as CD44 or Gr-1 can initiate a rapid self-elimination program in granulocytes through engagement of the coagulation system. We conclude that the robust anti-inflammatory effect of CD44-specific antibodies in arthritis is primarily due to their ability to trigger granulocyte depletion.
