Dongeon Kim

All Publications

• Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation. Circulation Kim, D., Tian, W., Wu, T. T., Xiang, M., Vinh, R., Chang, J. L., Gu, S., Lee, S., Zhu, Y., Guan, T., Schneider, E. C., Bao, E., Dixon, J. B., Kao, P., Pan, J., Rockson, S. G., Jiang, X., Nicolls, M. R. 2023

  Abstract

  Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation. Characterizing this biology is relevant for developing much needed therapies.Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1-deficient (S1pr1LECKO) mice were generated. Disease progression was quantified by tail-volumetric and -histopathologic measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then cocultured with CD4 T cells, followed by an analysis of CD4 T-cell activation and pathway signaling. Last, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T-cell activation.Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1P receptor 1 (S1PR1). LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T-cell infiltration in mouse lymphedema. LECs, isolated from S1pr1LECKO mice and cocultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs promoted T-helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. Human dermal LECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro, P-selectin blockade reduced the activation and differentiation of Th cells cocultured with shS1PR1-treated human dermal LECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema.This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T-cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.

  View details for DOI 10.1161/CIRCULATIONAHA.123.064181

  View details for PubMedID 37609838

• Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation. medRxiv : the preprint server for health sciences Kim, D., Tian, W., Wu, T. T., Xiang, M., Vinh, R., Chang, J., Gu, S., Lee, S., Zhu, Y., Guan, T., Schneider, E. C., Bao, E., Dixon, J. B., Kao, P., Pan, J., Rockson, S. G., Jiang, X., Nicolls, M. R. 2023

  Abstract

  BACKGROUND: Lymphedema is a global health problem with no effective drug treatment. Enhanced T cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T cell activation. Characterizing this biology is relevant for developing much-needed therapies.METHODS: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1 -deficient ( S1pr1 LECKO ) mice were generated. Disease progression was quantified by tail-volumetric and -histopathological measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then co-cultured with CD4 T cells, followed by an analysis of CD4 T cell activation and pathway signaling. Finally, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T cell activation.RESULTS: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1PR1. LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T cell infiltration in mouse lymphedema. LECs, isolated from S1pr1 LECKO mice and co-cultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs (HDLECs) promoted T helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. HDLECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro , P-selectin blockade reduced the activation and differentiation of Th cells co-cultured with sh S1PR1 -treated HDLECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema.CONCLUSION: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.Clinical Perspective: What is New?: Lymphatic-specific S1pr1 deletion exacerbates lymphatic vessel malfunction and Th1/Th2 immune responses during lymphedema pathogenesis. S1pr1 -deficient LECs directly induce Th1/Th2 cell differentiation and decrease anti-inflammatory Treg populations. Peripheral dermal LECs affect CD4 T cell immune responses through direct cell contact.LEC P-selectin, regulated by S1PR1 signaling, affects CD4 T cell activation and differentiation.P-selectin blockade improves lymphedema tail swelling and decreases Th1/Th2 population in the diseased skin.What Are the Clinical Implications?: S1P/S1PR1 signaling in LECs regulates inflammation in lymphedema tissue.S1PR1 expression levels on LECs may be a useful biomarker for assessing predisposition to lymphatic disease, such as at-risk women undergoing mastectomyP-selectin Inhibitors may be effective for certain forms of lymphedema.

  View details for DOI 10.1101/2023.06.08.23291175

  View details for PubMedID 37398237

• Lymph node fibroblastic reticular cells regulate differentiation and function of CD4 T cells via CD25. The Journal of experimental medicine Kim, D., Kim, M., Kim, T. W., Choe, Y., Noh, H. S., Jeon, H. M., Kim, H., Lee, Y., Hur, G., Lee, K., Shin, K., Lee, S., Lee, S. 2022; 219 (5)

  Abstract

  Lymph node fibroblastic reticular cells (LN-FRCs) provide functional structure to LNs and play important roles in interactions between T cells and antigen-presenting cells. However, the direct impact of LN-FRCs on naive CD4+ T cell differentiation has not been explored. Here, we show that T cell zone FRCs of LNs (LN-TRCs) express CD25, the alpha chain of the IL-2 receptor heterotrimer. Moreover, LN-TRCs trans-present IL-2 to naive CD4+ T cells through CD25, thereby facilitating early IL-2-mediated signaling. CD25-deficient LN-TRCs exhibit attenuated STAT5 phosphorylation in naive CD4+ T cells during T cell differentiation, promoting T helper 17 (Th17) cell differentiation and Th17 response-related gene expression. In experimental autoimmune disease models, disease severity was elevated in mice lacking CD25 in LN-TRCs. Therefore, our results suggest that CD25 expression on LN-TRCs regulates CD4+ T cell differentiation by modulating early IL-2 signaling of neighboring, naive CD4+ T cells, influencing the overall properties of immune responses.

  View details for DOI 10.1084/jem.20200795

  View details for PubMedID 35315876

• Exploring disease interrelationships in patients with lymphatic disorders: A single center retrospective experience. Clinical and translational medicine Rockson, S. G., Zhou, X., Zhao, L., Hosseini, D. K., Jiang, X., Sweatt, A. J., Kim, D., Tian, W., Snyder, M. P., Nicolls, M. R. 2022; 12 (4): e760

  Abstract

  The lymphatic contribution to the circulation is of paramount importance in regulating fluid homeostasis, immune cell trafficking/activation and lipid metabolism. In comparison to the blood vasculature, the impact of the lymphatics has been underappreciated, both in health and disease, likely due to a less well-delineated anatomy and function. Emerging data suggest that lymphatic dysfunction can be pivotal in the initiation and development of a variety of diseases across broad organ systems. Understanding the clinical associations between lymphatic dysfunction and non-lymphatic morbidity provides valuable evidence for future investigations and may foster the discovery of novel biomarkers and therapies.We retrospectively analysed the electronic medical records of 724 patients referred to the Stanford Center for Lymphatic and Venous Disorders. Patients with an established lymphatic diagnosis were assigned to groups of secondary lymphoedema, lipoedema or primary lymphovascular disease. Individuals found to have no lymphatic disorder were served as the non-lymphatic controls. The prevalence of comorbid conditions was enumerated. Pairwise co-occurrence pattern analyses, validated by Jaccard similarity tests, was utilised to investigate disease-disease interrelationships.Comorbidity analyses underscored the expected relationship between the presence of secondary lymphoedema and those diseases that damage the lymphatics. Cardiovascular conditions were common in all lymphatic subgroups. Additionally, statistically significant alteration of disease-disease interrelationships was noted in all three lymphatic categories when compared to the control population.The presence or absence of a lymphatic disease significantly influences disease interrelationships in the study cohorts. As a physiologic substrate, the lymphatic circulation may be an underappreciated participant in disease pathogenesis. These relationships warrant further, prospective scrutiny and study.

  View details for DOI 10.1002/ctm2.760

  View details for PubMedID 35452183

• Hypoxia and Hypoxia-Inducible Factors in Lymphedema. Frontiers in pharmacology Jiang, X., Tian, W., Kim, D., McQuiston, A. S., Vinh, R., Rockson, S. G., Semenza, G. L., Nicolls, M. R. 2022; 13: 851057

  Abstract

  Lymphedema is a chronic inflammatory disorder characterized by edema, fat deposition, and fibrotic tissue remodeling. Despite significant advances in lymphatic biology research, our knowledge of lymphedema pathology is incomplete. Currently, there is no approved pharmacological therapy for this debilitating disease. Hypoxia is a recognized feature of inflammation, obesity, and fibrosis. Understanding hypoxia-regulated pathways in lymphedema may provide new insights into the pathobiology of this chronic disorder and help develop new medicinal treatments.

  View details for DOI 10.3389/fphar.2022.851057

  View details for PubMedID 35450048

• The Role of Regulatory T Cells in Pulmonary Arterial Hypertension. Frontiers in immunology Tian, W., Jiang, S. Y., Jiang, X., Tamosiuniene, R., Kim, D., Guan, T., Arsalane, S., Pasupneti, S., Voelkel, N. F., Tang, Q., Nicolls, M. R. 2021; 12: 684657

  Abstract

  Pulmonary arterial hypertension (PAH) is a chronic, incurable condition characterized by pulmonary vascular remodeling, perivascular inflammation, and right heart failure. Regulatory T cells (Tregs) stave off autoimmunity, and there is increasing evidence for their compromised activity in the inflammatory milieu of PAH. Abnormal Treg function is strongly correlated with a predisposition to PAH in animals and patients. Athymic Treg-depleted rats treated with SU5416, an agent causing pulmonary vascular injury, develop PAH, which is prevented by infusing missing CD4+CD25highFOXP3+ Tregs. Abnormal Treg activity may also explain why PAH disproportionately affects women more than men. This mini review focuses on the role of Tregs in PAH with a special view to sexual dimorphism and the future promise of Treg therapy.

  View details for DOI 10.3389/fimmu.2021.684657

  View details for PubMedID 34489935

• Leukotrienes in Tumor-Associated Inflammation. Frontiers in pharmacology Tian, W., Jiang, X., Kim, D., Guan, T., Nicolls, M. R., Rockson, S. G. 2020; 11: 1289

  Abstract

  Leukotrienes are biologically active eicosanoid lipid mediators that originate from oxidative metabolism of arachidonic acid. Biosynthesis of leukotrienes involves a set of soluble and membrane-bound enzymes that constitute a machinery complex primarily expressed by cells of myeloid origin. Leukotrienes and their synthetic enzymes are critical immune modulators for leukocyte migration. Increased concentrations of leukotrienes are implicated in a number of inflammatory disorders. More recent work indicates that leukotrienes may also interact with a variety of tissue cells, contributing to the low-grade inflammation of cardiovascular, neurodegenerative, and metabolic conditions, as well as that of cancer. Leukotriene signaling contributes to the active tumor microenvironment, promoting tumor growth and resistance to immunotherapy. This review summarizes recent insights into the intricate roles of leukotrienes in promoting tumor growth and metastasis through shaping the tumor microenvironment. The emerging possibilities for pharmacological targeting of leukotriene signaling in tumor metastasis are considered.

  View details for DOI 10.3389/fphar.2020.01289

  View details for PubMedID 32973519

  View details for PubMedCentralID PMC7466732

• Leukotrienes in Tumor-Associated Inflammation FRONTIERS IN PHARMACOLOGY Tian, W., Jiang, X., Kim, D., Guan, T., Nicolls, M. R., Rockson, S. G. 2020; 11

  View details for DOI 10.3389/fphar.2020.01289

  View details for Web of Science ID 000566179100001

• Decreased lymphatic HIF-2α accentuates lymphatic remodeling in lymphedema. The Journal of clinical investigation Jiang, X. n., Tian, W. n., Granucci, E. J., Tu, A. B., Kim, D. n., Dahms, P. n., Pasupneti, S. n., Peng, G. n., Kim, Y. n., Lim, A. H., Espinoza, F. H., Cribb, M. n., Dixon, J. B., Rockson, S. G., Semenza, G. L., Nicolls, M. R. 2020

  Abstract

  Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor (HIF)-1α, but a reduction of HIF-2α protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif-2α exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif-2α caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2α is an important mediator of lymphatic health. HIF-2α promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (Angpt1) gene therapy. Our study suggests that HIF-2α normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2α pathways in lymphedema could mitigate long-term pathology and disability.

  View details for DOI 10.1172/JCI136164

  View details for PubMedID 32673288