Cytokine control of the synovial infiltrate is a central process in the development of inflammatory arthritis. In this study, we combine genetic approaches and intervention strategies to describe a fundamental requirement for IL-6-mediated STAT3 signaling in orchestrating the inflammatory infiltrate in monoarticular and systemic models of experimental arthritis. STAT3 activation via the common gp130 signal-transducing receptor for all IL-6-related cytokines led to increased retention of neutrophils and T cells within the inflamed synovium, which included STAT3-regulated IL-17A-secreting T cells. Control of leukocyte infiltration was reliant upon IL-6 signaling via its soluble receptor (termed IL-6 trans signaling), as evidenced by selective blockade of this alternative IL-6 signaling pathway using an engineered variant of soluble gp130 (sgp130Fc). This therapeutic intervention led to substantial clinical improvement in mice with emerging or established incidence of systemic arthritis. These data illustrate that IL-6 control of STAT3 is critical for regulating the synovial infiltrate in inflammatory arthritis, and suggest that selective inhibition of IL-6 trans signaling may provide a more refined intervention strategy for blocking IL-6-driven proarthritic activities.

Assessment of the vigour, vitality or viability of microorganisms must be done on an individual basis and thus requires the non‐invasive interrogation of single organisms. For suspended organisms, flow cytometry provides a powerful means of measurement of a wide range of characteristics. Similar information for microbes in aggregates or growing on surfaces may be obtained by use of confocal scanning laser microscopy. For instance, membrane potential‐sensitive fluorophores can distinguish between vigorous, frail and dead cells.

The annulus fi brosus of the intervertebral disc is a complex, radial-ply connective tissue consisting of concentric lamellae of oriented collagen. Whilst much is known of the structure of the mature annulus, less is known of how its complex collagenous architecture becomes established; an understanding of which could inform future repair/ regenerative strategies. Here, using a rat disc developmental series, we describe events in the establishment of the collagenous framework of the annulus at light and electron microscopic levels and examine the involvement of class I and II small leucine rich proteoglycans (SLRPs) in the matrix assembly process. We show that a period of sustained, ordered matrix deposition follows the initial cellular differentiation/orientation phase within the foetal disc. Fibrillar matrix is deposited from recesses within the plasma membrane into compartments of interstitial space within the outer annulus -the orientation of the secreted collagen refl ecting the initial cellular orientation of the laminae. Medially, we demonstrate the development of a reinforcing 'cage' of collagen fi bre bundles around the foetal nucleus pulpous. This derives from the fusion of collagen bundles between presumptive end-plate and inner annulus. By birth, the distinct collagenous architectures are established and the disc undergoes considerable enlargement to maturity. We show that fi bromodulin plays a prominent role in foetal development of the annulus and its attachment to vertebral bodies. With the exception of keratocan, the other SLRPs appear associated more with cartilage development within the vertebral column, but all become more prominent within the disc during its growth and differentiation.

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