Background/Purpose: Lupus is a chronic autoimmune disease with a global loss of self-tolerance. Lupus patients are photosensitive where exposure to even ambient sunlight results in skin inflammation. Lymph carries signals such as antigens and antigen-presenting cells from the skin to the lymph node. We recently demonstrated that exposure to ultraviolet radiation (UVR) causes reduced lymph flow from skin to lymph node in lupus mouse models and that improving flow reduced B and T cell responses by increasing fibroblastic reticular cell (FRC) CCL2 expression and FRC proliferation (Howlader, Ambler et al. Journal of Clinical Investigation, vol. 135, no. 10, 2025, e168412). How improved flow can affect the lymph node stromal compartment is not understood. Migratory dendritic cells (DCs) travel in the lymph from skin to lymph node, where they can change FRC phenotype. Reduced interferon signaling results in increased FRC CCL2 expression and increased expansion of FRCs. Here, we hypothesize that improving lymph flow allows for more migratory DCs to mediate FRC proliferation through reduced interferon signaling.

Methods: We used an inducible lupus mouse model where topical imiquimod (a TLR7 agonist) induces a lupus-like phenotype with elevated type I IFN signaling. Mice were exposed to UVR 4 days/week to study photosensitivity. We improve flow through manual lymphatic drainage (MLD), which is a light skin stretching technique that helps promote the movement of lymphatic fluid out of a swollen area. To assess the role of DCs, we generated bone marrow chimeras using zDC-DTR donors into B6 recipients, enabling selective depletion of DCs via diphtheria toxin (DT). We analyzed LN immune and stromal populations by flow cytometry and quantified interferon stimulated gene (ISG) expression by qPCR.

Results: Improving lymph flow increased the number of migratory dendritic cells in the lymph node and not Langerhans cells or resident dendritic cells. Depletion of migratory dendritic cells prior to MLD reversed the FRC proliferation, indicating that migratory DCs are required for FRC proliferation. MLD led to reduced expression of lymph node ISGs and adding interferon reverses MLD induced FRC expansion. We currently are investigating if migratory dendritic cells are required for the reduced interferon signaling.

Conclusion: Our results support a potential DC-stromal axis that plays a role in lupus photosensitivity. Imporving lymphatic flow promotes migratory DC entry into LNs, which appears to suppress IFN signaling and promote FRC proliferation. These findings highlight a lymphatic-dendritic cell-stromal axis as a potential therapeutic target to alleviate photosensitivity-associated autoimmunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/improved-skin-lymphatic-flow-regulates-dendritic-cells-to-mediate-lymph-node-fibroblast-alterations-and-immune-responses-in-lupus/