Background/Purpose: A wide variety of systemic pathologies, including infectious and autoimmune diseases, are accompanied by joint pain or inflammation, often mediated by circulating immune complexes (IC). The synovial membrane contains a rich vascular network and also contains abundant pain fibres. However, how systemic immune challenges gain access to the synovium and whether or how the triggering of arthralgia-generating pain neurons in response to circulating stimuli is influenced by synovial immune cells, or how immune cells in turn, might be affected by pain, is currently unknown.

Methods: We established a protocol to stereotactically dissect the entire synovium, and to undertake whole mount synovial imaging, as an improved alternative to standard sagittal joint sections, to enable a comprehensive assessment of the spatial arrangement of immune cells relative to the neurovascular structures of the synovium. Systemic immune challenges were induced by intravenous injection of fluorescently labeled IC and microbeads, or oral challenge with Salmonella typhimurium. Whole mount synovial imaging, single cell RNA-seq, and ex vivo culture system of the synovium and sensory neurons from dorsal root ganglia were performed to analyse the spatial, transcriptional, and proteomic information of immune cells, endothelial cells, and nociceptor neurons. In vivo manipulation of FcγR signal strength was performed in FcγRⅡb-deficient mice.

Results: Highly permeable PV1⁺ capillaries were specifically located at the lining-sublining interface, in the periphery of the synovium, enabling entry of circulating stimuli into the joint. This area of vulnerability was occupied by nociceptor neurons and three subsets of macrophages that demonstrated distinct responses to systemic IC challenge. In vivo manipulation of macrophage FcgR signal strength determined the magnitude of synovial inflammation. Nociceptor activation led to CGRP production, which enhanced macrophage cluster formation upon bloodborne immune challenges, producing a physical cellular barrier to defend the area of vulnerability around PV1⁺ capillaries.

Conclusion: The unique anatomical arrangement in the peripheral region of the synovium provides access to circulating immune stimuli, and this is policed by interacting macrophages and nociceptor neurons, forming a blood-joint barrier (BJB) to defend joint tissue.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/macrophages-and-nociceptor-neurons-form-a-sentinel-unit-around-fenestrated-capillaries-to-defend-the-synovium-from-systemic-challenges/