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Immigration check for neutrophils in RA lining: laminin α5 low expression regions act as exit points

Objective: A correlation exists between the absence of α5-laminin and transit checkpoint fenestrations in vascular basement membranes. We hypothesized that similar laminin α5 low expression regions might exist in synovial lining, which, although lacking basement membrane, contains all basement membrane components in its interstitial matrix. Methods: Laminin α4 and α5 chains and lactoferrin were stained using immunofluorescence and cathepsin G and neutrophil elastase using immunoperoxidase. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure laminin α4 and α5 mRNA copy numbers in cultured synovial fibroblasts, without/with tumour necrosis factor-α (TNFα) and interleukin-1β (IL-1β). Results: Laminin α4 and α5 chains were found in the intercellular matrix in synovial lining samples of trauma and revision total hip replacements. Laminin α5 was weaker in osteoarthritis (OA) and rheumatoid arthritis (RA), and RA synovial lining also contained local low expression areas. Double staining disclosed convergence of lactoferrin-degranulating neutrophils towards these laminin α5 low expression regions. In cultured OA synovial fibroblasts, laminin α5 mRNA decreased (p < 0.05) at 1 ng/mL TNFα and was not found at all in cultured resting or cytokine-stimulated RA fibroblasts. Degranulation of cathepsin G and neutrophil elastase was seen in neutrophils passing through blood vessels or synovial lining. Conclusions: Migrating neutrophils in RA seem to use laminin α5 chain low expression regions to exit synovial tissue to enter synovial fluid. Transmigrating neutrophils remodel the intercellular matrix by releasing their proteolytic granular contents to enhance these low expression checkpoints and/or to produce chemotactic stimuli. In RA fibroblasts this is facilitated by cytokine-mediated down-regulation or lack of laminin α5 synthesis.