CCL19-Positive Lymph Node Stromal Cells Govern the Onset of Inflammatory Arthritis via Tropomyosin Receptor Kinase.

OBJECTIVE: The study objective was to assess the role of CCL19+ lymph node stromal cells of the joint-draining popliteal lymph node (pLN) for the development of arthritis. METHODS: CCL19+ lymph node stromal cells were spatiotemporally depleted for five days in the pLN before the onset of collagen-induced arthritis (CIA) using Ccl19-Cre × iDTR mice. In addition, therapeutic treatment with recombinant CCL19-immunoglobulin G (IgG), locally injected in the footpad, was used to confirm the results. RNA sequencing of lymph node stromal cells combined with T cell coculture assays using tropomyosin receptor kinase (Trk) family inhibitors together with in vivo local pLN small interfering RNA (siRNA) treatments were used to elucidate the pathway by which CCL19+ lymph node stromal cells initiate the onset of arthritis. RESULTS: Spatiotemporal depletion of CCL19+ lymph node stromal cells prevented disease onset in CIA mice. These inhibitory effects could be mimicked by local CCL19-IgG treatment. The messenger RNA sequencing analyses showed that CCL19+ lymph node stromal cells down-regulated the expression of the tropomyosin receptor kinase A (TrkA) just before disease onset. Blocking TrkA in lymph node stromal cells led to increased T cell proliferation in in vitro coculture assays. Similar effects were observed with the pan-Trk inhibitor larotrectinib in cocultures of lymph node stromal cells of patients with rheumatoid arthritis and T cells. Finally, local pLN treatment with TrkA inhibitor and TrkA siRNA led to exacerbated arthritis scores. CONCLUSION: CCL19+ lymph node stromal cells are crucially involved in the development of inflammatory arthritis. Therefore, targeting of CCL19+ lymph node stromal cells via TRK could provide a tool to prevent arthritis.

Assessing visual modulation along the human subcortical auditory pathway.

Experience of the world is inherently multisensory. It has been suggested that audiovisual modulation occurs as early as subcortical auditory stages. However, this was based on the frequency-following response, a measure recently found to be significantly generated from cortical sources. It therefore remains unclear whether subcortical auditory processing can indeed be modulated by visual information. We aimed to trace visual modulation along the auditory pathway by comparing auditory brainstem response (ABR) and middle-latency response (MLR) between unimodal auditory and multimodal audiovisual conditions. EEG activity was recorded while participants attended auditory clicks and visual flashes, either synchronous or asynchronous. No differences between auditory and audiovisual responses were observed at ABR or MLR levels. It suggested that ascending auditory processing does not seem to be modulated by visual cues at subcortical levels, at least for rudimentary stimuli. Multimodal modulation in the auditory brainstem observed in previous studies might therefore originate from cortical sources and top-down processes. More studies are needed to further disentangle subcortical and cortical influences on audiovisual modulation along the auditory pathway.