Manifestations of Inflammatory Arthritis Are Critically Dependent on LFA-1

Abstract

Leukocyte infiltration of synovial fluid and tissues is the hallmark of inflammatory arthritis. Selectins and β2 integrins have been implicated in the multistep process of leukocyte adhesion to vascular endothelium. However, previous work has revealed disparate requirements for leukocyte recruitments to specific anatomic locales. Moreover, the mechanisms regulating recruitment of leukocytes to the joint in inflammatory arthritis models are not fully understood. We hypothesized that β2 integrins, expressed on leukocytes, might play a pathogenic role in synovial inflammation. Using mice deficient in all β2 integrins (CD18 null mice), we demonstrate that expression of these heterodimeric adhesion molecules is critical for arthritis induction in the K/B × N serum transfer model. Using null-allele mice and blocking mAbs, we demonstrate specifically that CD11a/CD18 (LFA-1) is absolutely required for the development of arthritis in this model. Blocking mAbs further revealed an ongoing requirement for LFA-1 I-domain adhesive function in disease perpetuation. These findings suggest that the LFA-1 I-domain forms an attractive target for treatment of human inflammatory arthritis.

Coexpression of two mesenchymal cadherins, cadherin 11 and N‐cadherin, on murine fibroblast‐like synoviocytes

“…For immunohistochemical analyses, ankle tissue samples were fixed in 4% paraformaldehyde in phosphate buffered saline for 24 hours and decalcified with Kristensen's solution for 48 hours (16). Tissue samples were dehydrated, embedded in paraffin, and cut into 5-m-thick sections.…”

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…LFA-1, a ␤2 integrin, is critical in the development of inflammatory arthritis in the K/BxN serum transfer mouse model of arthritis. Ablating LFA-1, either by using a CD11a-null mouse or by coadministration of K/BxN serum with monoclonal antibodies to LFA-1, prevents induction of (and ameliorates established) disease (51). When statins (excepting pravastatin, which does not interact with the L-site) bind to LFA-1, they effect allosteric changes in the integrin that prevent ICAM-1 binding.…”

Regulation of dextran sodium sulfate induced colitis by leukocyte beta 2 integrins

“…Data from our lab and others using mouse models of arthritis, SLE, psoriasis, and autoimmune diabetes show that the b 2 integrins serve as the dominant adhesion molecules involved in chronic immune cell recruitment and activation, despite prominent expression of other known leukocyte adhesion proteins (eg VLA-4). 12,13,15,20 However, the pathological importance of b 2 integrin regulation of leukocyte recruitment and function during experimental colitis is not known.…”