Blood neutrophils express VLA-4 and it mediates migration to arthritic joint and dermal inflammation

The migration of neutrophils (PMNs) out of the blood to inflamed joints is mediated by both CDI8 integrins and a CD18 independent pathway. To investigate this migration radiolabelled rat blood PMNs were used to measure PMN accumulation in the inflamed joints of rats with adjuvant arthritis and in dermal inflammatory sites. PMNs migrated rapidly (<2h) to inflamed joints and monoclonal antibodies (mAb) to LFA-1 and Mac-1 together or anti-CD 18 inhibited only 50-75% of this PMN accumulation. However, these mAbs inhibited PMN migration to intradermal C5ato , TNFa, LPS and poly 1:C by 90%. Flow cytometry demonstrated low levels of VLA-4 on nearly all rat blood PMNs. Anti-VLA-4 plus anti-LFA-1, but neither mAb alone, strongly inhibited PMN accumulation in arthritic joints. VLA-4 plus LFA-1 blockade also inhibited 30-70 % of PMN migration to dermal inflammation. Anti-VLA-4 together with CD18 blockade virtually abolished (95-99%) PMN accumulation in cutaneous sites. However, blocking both VLA-4 and CD18 decreased PMN accumulation in the inflamed joints by 70-80% leaving a significant portion of PMN accumulation. In conclusion, rat blood PMNs express functional VLA-4 which can mediate PMN migration to both inflamed joints and dermal inflammation. VLA-4 can substitute for LFA-1 and is particularly important in PMN migration in chronic inflammation. However, there is also an additional CD 18 and VLA-4 independent pathway of PMN migration to arthritic joints.