Thursday, May 1, 2025
5/1/2025
Lymphatic regulation of lymph node function in lupus - Patients with systemic lupus erythematosus (SLE) are photosensitive, demonstrating an increased skin sensitivity to ultraviolet radiation (UVR) whereby even ambient exposure to sunlight can result in the development of inflammatory skin lesions. Beyond the skin, however, UVR exposure can also trigger systemic disease flares, with increased circulating autoantibodies and further injury of end organs. The mechanisms by which UVR exposure at the skin can lead to flares of systemic autoimmunity are not well understood. Our long-term goal is to delineate the mechanisms that connect photosensitivity with systemic disease flares. Skin communicates with the immune system via lymphatic vessels which serve both to remove interstitial fluid from skin and bring antigens and mediators to regulate draining lymph node immune function. Compromised lymphatic flow results in increased and prolonged skin inflammation and alters the signals that reach the lymph nodes, resulting in autoantibody generation over the long term. The importance of lymphatic flow in both skin and lymph node regulation led us to examine lymphatic flow function in SLE. We show evidence of compromised lymphatic flow in human SLE and multiple mouse models and that improving lymphatic flow in SLE models reduces skin photosensitivity and draining lymph node plasmablast responses. Our goal with this proposal is to understand the mechanisms by which lymphatic flow regulates draining lymph node immune responses in lupus-like disease. We show preliminary data that improving lymphatic flow increases lymph node fibroblastic reticular cell (FRC) expression of CCL2, driving the FRC-monocyte-plasmablast axis that limits plasmablast survival. Improving lymphatic flow also downregulated skin interferon-I (IFN-I)-stimulated gene expression and upregulated FRC CCL2 was dependent on the NOX2 subunit of NADPH oxidase. Improving lymphatic flow additionally upregulated FRC expression of IMP2, an RNA binding protein that detects N6-methyladenosine RNA modifications and stabilizes CCL2 mRNA, and regulatory T cell accumulation in lymph nodes. These data suggest the following hypothesis: Improving lymphatic flow reduces IFN-I signaling, upregulating FRC NOX2-mediated reactive oxygen species generation that drives an IMP2-mediated program of FRC alterations. The resulting FRC CCL2 upregulation modulates monocyte and regulatory T cell function in lymph nodes, limiting B cell responses. Our aims are to 1) delineate the relationship between IFN-I and Nox2 in regulating FRC CCL2, 2) Understand the extent of contributions of IMP2 to lymphatic-driven FRC phenotypic alterations, and 3) understand the mechanisms by which lymphatic- driven FRC regulation reduces B cell responses. The proposal will help us understand how lymphatic function contributes to lupus-like disease and delineate mechanisms by which FRCs are regulated and shape lymph node function, paving the way to better understanding the relationship between photosensitivity and autoimmunity.
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