Improving lymphatic flow in SLE mice induces fibroblastic reticular cell survival via lymphotoxin beta receptor signaling.

Abstract

Abstract Systemic lupus erythematosus (SLE) patients are photosensitive, where ultraviolet radiation (UVR) exposure can induce skin inflammation and also trigger systemic disease flares. The link between photosensitive skin and systemic autoimmunity is not well understood. Skin communicates with the immune system via lymphatic vessels that carry lymph into the conduit system of lymph nodes (LNs), which is ensheathed by fibroblastic reticular cells (FRCs). FRCs play critical roles in limiting T and B cell responses. Dendritic cells (DCs) interact both with lymphatic fluid and with FRCs and can modulate FRC survival and numbers via a DC-lymphotoxin beta receptor (LTβR)-FRC axis. We have recently shown dysfunctional lymphatic flow in human SLE and SLE mouse models exposed to UVR and that improving lymphatic flow via manual lymphatic drainage (MLD) reduces skin photosensitivity and LN plasmablast responses, while increasing FRC numbers. In this study, we aim to delineate the mechanism by which MLD induces FRC alterations, hypothesizing that it is via the DC-LTβR-FRC axis. Currently, we have found that MLD increases FRC survival of UVR exposed mice. However, treatment with antagonist LTbR-Ig reverses this FRC survival, suggesting that MLD induces FRC survival via LTbR signaling. Ongoing experiments are targeting the importance of DCs and DC-derived LTβ in modulating MLD-induced changes to FRCs. The novelty of this study is in showing that lymphatic flow from the skin can influence stromal cell populations in SLE. These findings will improve our understanding of the relationship between photosensitivity and systemic autoimmunity.