Lymphatic dysfunction in lupus contributes to cutaneous photosensitivity and lymph node B cell responses
Mir J. Howlader, William G. Ambler, Madhavi Latha S. Chalasani, Aahna Rathod, Ethan S. Seltzer, Ji Hyun Sim, Jinyeon Shin, Noa Schwartz, William D. Shipman III, Dragos C. Dasoveanu, Camila B. Carballo, Ecem Sevim, Salma Siddique, Yurii Chinenov, Scott A. Rodeo, Doruk Erkan, Raghu P. Kataru, Babak J. Mehrara, Theresa T. Lu
Mir J. Howlader, William G. Ambler, Madhavi Latha S. Chalasani, Aahna Rathod, Ethan S. Seltzer, Ji Hyun Sim, Jinyeon Shin, Noa Schwartz, William D. Shipman III, Dragos C. Dasoveanu, Camila B. Carballo, Ecem Sevim, Salma Siddique, Yurii Chinenov, Scott A. Rodeo, Doruk Erkan, Raghu P. Kataru, Babak J. Mehrara, Theresa T. Lu
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Research Article Autoimmunity Immunology Inflammation Vascular biology

Lymphatic dysfunction in lupus contributes to cutaneous photosensitivity and lymph node B cell responses

Abstract

Patients with systemic lupus erythematosus (SLE) are photosensitive, developing skin inflammation with even ambient ultraviolet radiation (UVR), and this cutaneous photosensitivity can be associated with UVR-induced flares of systemic disease, which can involve increased autoantibodies and further end-organ injury. Mechanistic insight into the link between the skin responses and autoimmunity is limited. Signals from skin are transmitted directly to the immune system via lymphatic vessels, and here we show evidence for potentiation of UVR-induced lymphatic flow dysfunction in SLE patients and murine models. Improving lymphatic flow by manual lymphatic drainage (MLD) or with a transgenic model with increased lymphatic vessels reduces both cutaneous inflammation and lymph node B and T cell responses, and long-term MLD reduces splenomegaly and titers of a number of autoantibodies. Mechanistically, improved flow restrains B cell responses in part by stimulating a lymph node fibroblastic reticular cell-monocyte axis. Our results point to lymphatic modulation of lymph node stromal function as a link between photosensitive skin responses and autoimmunity and as a therapeutic target in lupus, provide insight into mechanisms by which the skin state regulates draining lymph node function, and suggest the possibility of MLD as an accessible and cost-effective adjunct to add to ongoing medical therapies for lupus and related diseases.

Authors

Mir J. Howlader, William G. Ambler, Madhavi Latha S. Chalasani, Aahna Rathod, Ethan S. Seltzer, Ji Hyun Sim, Jinyeon Shin, Noa Schwartz, William D. Shipman III, Dragos C. Dasoveanu, Camila B. Carballo, Ecem Sevim, Salma Siddique, Yurii Chinenov, Scott A. Rodeo, Doruk Erkan, Raghu P. Kataru, Babak J. Mehrara, Theresa T. Lu

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Figure 5

Improving lymphatic flow increases lymph node FRC proliferation, FRC CCL2, monocyte ROS generation, and limits plasmablast numbers in a monocyte-dependent manner.

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Improving lymphatic flow increases lymph node FRC proliferation, FRC CCL...
(A–Q) Left auricular lymph nodes of indicated mice exposed to 4 days of UVR were examined. (A) FRC expression of GFP in CCL2-GFP reporter mice treated with IMQ that received MLD or control handling with UVR. (B) CCL2 expression by FRCs in LECPTEN-IMQ and LECWT- IMQ mice. (A and B) Representative histograms (left) and graphs (right). MFI, geometric mean fluorescence intensity. (C–G) B6-IMQ mice received 4 days of +/-MLD with UVR. (C) FRC numbers. (D) Percentage of FRCs that express Ki-67, (E) normalized to control handled mice. (F) Ly6Chi monocyte numbers, flow cytometry gating (left), and numbers (right). (G) Monocyte ROS measured using CM-H2DCFDA, representative histograms (left) and relative MFI of CM-H2DCFDA (right). (H–L) B6-IMQ mice were treated with anti-Gr-1 or isotype control at days –1, 0, and +2 of UVR and MLD treatments as shown in H. (I) Monocyte numbers and (J) normalized to isotype control. (K) Germinal center B cell and (I) plasmablast numbers. (M–Q) CCR2-DTR mice were treated with DT at days 0 and 2 of UVR and MLD treatments as shown in M. (N) Monocyte numbers and (O) normalized to control. (P) Germinal center B cell and (Q) plasmablast numbers. Each symbol represents 1 mouse; n = 6 to 19 per condition; data are from 2 (B), 3 (A and I–L), 5 (N and O), 6 (D–G, P, and Q), and 7 (C) independent experiments. Normality was assessed using the Shapiro-Wilk test. If normal, unpaired t test was used. If data were not normal, Mann-Whitney U test was used. ***P < 0.001; **P < 0.01; *P < 0.05. Error bars represent SD.