CD44-specific antibody treatment and CD44 deficiency exert distinct effects on leukocyte recruitment in experimental arthritis.
CD44, the leukocyte adhesion receptor for hyaluronan, has been considered 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, 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 cross-linking and are reproducible with an antibody against Gr-1, a molecule that, like CD44, is highly expressed on granulocytes. Anticoagulant pretreatment, which prevents platelet deposition, mitigates both granulocyte depletion and the suppressive effect of CD44-specific antibody on joint swelling. Our observations suggest that cross-linking 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 the result of their ability to trigger granulocyte depletion.
Hutás
Gábor
G
Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA.
Bajnok
Eva
E
Gál
István
I
Finnegan
Alison
A
Glant
Tibor T
TT
Mikecz
Katalin
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy* / Q000473:pathology; D001792:Blood Platelets; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006098:Granulocytes / Q000187:drug effects*; D018960:Hyaluronan Receptors / Q000276:immunology*; D007249:Inflammation / Q000188:drug therapy; D036904:Leukocyte Rolling / Q000187:drug effects*; D007962:Leukocytes; D051379:Mice; D008807:Mice, Inbred BALB C; D019707:Receptors, Chemokine / Q000276:immunology*
D000911:Antibodies, Monoclonal; C503133:Gr-1 protein, mouse; D018960:Hyaluronan Receptors; D019707:Receptors, Chemokine