Abstract
The inappropriate accumulation and activation of leukocytes is a shared pathological feature of immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Cellular accumulation is therefore an attractive target for therapeutic intervention. However, attempts to modulate leukocyte entry and exit from the joint have proven unsuccessful to date, indicating that gaps in our knowledge remain. Technological advancements are now allowing real-time tracking of leukocyte movement through arthritic joints or in vitro joint constructs. Coupling this technology with improvements in analyzing the cellular composition, location and interactions of leukocytes with neighboring cells has increased our understanding of the temporal dynamics and molecular mechanisms underpinning pathological accumulation of leukocytes in arthritic joints. In this review, we explore our current understanding of the mechanisms leading to inappropriate leukocyte trafficking in inflammatory arthritis, and how these evolve with disease progression. Moreover, we highlight the advances in imaging of human and murine joints, along with multi-cellular ex vivo joint constructs that have led to our current knowledge base.
Highlights
OVERVIEW OF THE LEUKOCYTE RECRUITMENT CASCADEOver the last 30 years, the general understanding of how leukocytes migrate out of the blood, across the endothelium and through inflamed tissues has been extensively researched providing us with a step by step cascade of events (Figure 1) (Ley et al, 2007; Vestweber, 2015)
We explore our current understanding of the mechanisms leading to inappropriate leukocyte trafficking in inflammatory arthritis, and how these evolve with disease progression
Chronic inflammatory arthritis is characterized by the aberrant accumulation and activation of such leukocytes within the synovial tissue, along with tissue-resident stromal cells becoming epigenetically reprogrammed, both of which drive tissue and bone damage leading to pain and immobility in patients with, for example, rheumatoid arthritis (RA) or psoriatic arthritis (PsA)
Summary
Over the last 30 years, the general understanding of how leukocytes migrate out of the blood, across the endothelium and through inflamed tissues has been extensively researched providing us with a step by step cascade of events (Figure 1) (Ley et al, 2007; Vestweber, 2015). In line with this, imaging techniques for analyzing the individual steps of the cascade, from leukocyte capture through to migration into the tissue, have improved exponentially giving us much more granularity on the temporal and dynamic kinetics of these events and the key molecules involved. The clinical urgency to identify new drug targets that limit the trafficking of pathogenic leukocytes and promote the entry of regulatory cells into chronically inflamed tissues, such as the joint, are partly responsible for driving forward the imaging techniques necessary to visualize these processes in real-time. We explore our current understanding of the mechanisms leading to inappropriate leukocyte trafficking in inflammatory arthritis, and how these evolve with disease progression
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