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

Ambler, William G; Chalasani, Madhavi Latha Somaraju; Seltzer, Ethan; Sim, JiHyun; Shin, Jinyeon; Schwartz, Noa; Dasoveanu, Dragos; Carballo, Camila; Sevim, Ecem; Rodeo, Scott A.; Erkan, Doruk; Kataru, Raghu P.; Mehrara, Babak J.; Lu, Theresa

doi:10.1101/2022.06.13.495930

Cited by 3 publications

(4 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study identified dysfunctional lymphatic flow as one of the factors that contribute to the pathophysiology of lupus (Ambler et al, 2022). The authors reported evidence of dysfunctional lymphatic flow in both murine and human models of SLE and concluded that this contributes to cutaneous photosensitivity and the activation of B cells in the lymph node in SLE (Ambler et al, 2022). This correlates with previous studies that reported a correlation between a reduction in lymphatic flow and skin inflammation (Kajiya and Detmar, 2006;Thomas et al, 2012).…”

Section: The Lymphatic System In Systemic Lupus Erythematosussupporting

confidence: 75%

“…If inflammation persists, the adipose tissue surrounding the lymph node expands (Baluk et al, 2009;Proulx et al, 2013;Zhang et al, 2007). A recent study identified dysfunctional lymphatic flow as one of the factors that contribute to the pathophysiology of lupus (Ambler et al, 2022). The authors reported evidence of dysfunctional lymphatic flow in both murine and human models of SLE and concluded that this contributes to cutaneous photosensitivity and the activation of B cells in the lymph node in SLE (Ambler et al, 2022).…”

Section: The Lymphatic System In Systemic Lupus Erythematosusmentioning

confidence: 99%

See 1 more Smart Citation

Leveraging Lymphatic System Targeting in Systemic Lupus Erythematosus for Improved Clinical Outcomes

Babalola,

Arora,

Ganugula

et al. 2023

Pharmacol Rev

View full text Add to dashboard Cite

The role of advanced drug delivery strategies in drug-repositioning and minimizing drug attrition rates, when applied early in drug discovery, is poised to increase the translational impact of various therapeutic strategies in disease prevention and treatment. In this context, drug delivery to the lymphatic system is gaining prominence not only to improve the systemic bioavailability of various pharmaceutical drugs but also to target certain specific diseases associated with the lymphatic system. While the role of the lymphatic system in lupus is known, very little is done to target drugs to yield improved clinical benefits. In this review, we discuss recent advances in drug delivery strategies to treat lupus, the various routes of drug administration leading to improved lymph node bioavailability, and the available technologies applied in other areas that can be adapted to lupus treatment. Moreover, this review also presents some recent findings that demonstrate the promise of lymphatic targeting in a preclinical setting, offering renewed hope for certain pharmaceutical drugs that are limited by efficacy in their conventional dosage forms. These findings underscore the potential and feasibility of such lymphatic drug targeting approaches, to enhance therapeutic efficacy in lupus and minimize off-target effects of the pharmaceutical drugs. Significance StatementThe World Health Organization estimates that there are currently 5 million humans living with some form of lupus. With limited success in lupus drug discovery, turning to effective delivery strategies with existing drug molecules, as well as those in the early stage of discovery, could lead to better clinical outcomes. After all, effective delivery strategies have been proven to improve treatment outcomes.

show abstract

Section: The Lymphatic System In Systemic Lupus Erythematosussupporting

confidence: 75%

Section: The Lymphatic System In Systemic Lupus Erythematosusmentioning

confidence: 99%

Leveraging Lymphatic System Targeting in Systemic Lupus Erythematosus for Improved Clinical Outcomes

Babalola,

Arora,

Ganugula

et al. 2023

Pharmacol Rev

View full text Add to dashboard Cite

show abstract

“…The IMQ model is induced by 4–5 weeks of topical IMQ, a TLR 7/8 agonist, resulting in autoantibody production, enlarged spleen and lymph nodes, nephritis, and photosensitivity characteristic of SLE ( Ambler et al, 2022 ; Goel et al, 2020 ; Yokogawa et al, 2014 ). The model can be induced in B6 mice, allowing for the use of transgenic models to assess for effects on lupus features without crossing onto a different genetic background.…”

Section: Resultsmentioning

confidence: 99%

The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus

Li,

Zyulina,

Seltzer

et al. 2024

eLife

Self Cite

View full text Add to dashboard Cite

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.

show abstract

“…We also tested for expression of ISGs in the imiquimod (IMQ) lupus model. This model is induced by 4-5 weeks of topical IMQ, a TLR 7/8 agonist, resulting in autoantibody production, enlarged spleen and lymph nodes, nephritis, and photosensitivity characteristic of SLE (Ambler et al, 2022; Goel et al, 2020; Yokogawa et al, 2014). The model can be induced in B6 mice, allowing for the use of transgenic models to assess for effects on lupus features without having to cross onto a different genetic background.…”

Section: Resultsmentioning

confidence: 99%

The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus

Veiga

Schwartz

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Type I IFN (IFN-I) mediates autoimmune and inflammatory conditions, and better understanding IFN-I-driven pathogenesis could expand therapeutic possibilities. Lupus is an autoimmune disease characterized by photosensitivity, inflammatory skin lesions, and systemic organ damage. Patients have an IFN-I signature in blood and tissues and anifrolumab (anti-IFNAR1), developed for lupus and recently FDA-approved, underscores the importance of IFN-I in pathogenesis. Anifrolumab is especially efficacious for cutaneous disease, but mechanisms are poorly understood. Langerhans cells (LCs) normally limit UVR-induced skin injury via ADAM17, a metalloprotease that clips from the cell membrane and activates skin-protective EGFR ligands. Downregulation of LC ADAM17 mRNA and activity in lupus models contributes to photosensitivity, and here we link IFN-I pathogenesis with LC dysfunction. We show that murine model and human lupus non-lesional skin have IFN-I signatures and that IFN-I reduces ADAM17 sheddase activity in LCs. Furthermore, anti-IFNAR1 in multiple murine lupus models restores LC ADAM17 function and reduces photosensitivity in an EGFR and LC ADAM17-dependent manner. These results suggest that IFN-I contributes to photosensitivity in lupus by downregulating LC ADAM17 function, providing mechanisms for IFN-I pathogenesis and anifrolumab efficacy and highlighting the importance of LCs as a potential therapeutic target.

show abstract

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

Cited by 3 publications

References 35 publications

Leveraging Lymphatic System Targeting in Systemic Lupus Erythematosus for Improved Clinical Outcomes

Leveraging Lymphatic System Targeting in Systemic Lupus Erythematosus for Improved Clinical Outcomes

The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus

The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus

Contact Info

Product

Resources

About