ALCAM Mediates DC Migration Through Afferent Lymphatics and Promotes Allospecific Immune Reactions

Willrodt, Ann Helen; Salabarria, Ann‐Charlott; Schineis, Philipp; Ignatova, Desislava; Hunter, Morgan Campbell; Vranova, Martina; Golding-Ochsenbein, Alexandra M.; Sigmund, Elena C.; Romagna, Annatina; Strassberger, Verena; Fabbi, Marina; Ferrini, Silvano; Cursiefen, Claus; Neri, Dario; Guenova, Emmanuella; Bock, Felix; Halin, Cornelia

doi:10.3389/fimmu.2019.00759

Cited by 30 publications

(40 citation statements)

References 55 publications

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“…Control groups were either treated with KSF-Fc, i.e. an Fc-fusion of a single-chain variable fragment (scFv) directed against hen egg lysozyme 37 , or dexamethasone (i.e. a corticosteroid).…”

Section: Resultsmentioning

confidence: 99%

“…Mice were treated i.p. with 37 μg mIL-7-Fc or corresponding control fusion protein (KSF-Fc; non-specific single chain Fv antibody fragment against hen egg lysozyme 53 , fused to an IgG1 Fc fragment, and produced in our lab 37 , or 400 μg anti-IL-7α blocking antibody (clone A7R34, Bioexcell, West Lebanon, USA) or corresponding IgG control (clone 2A3, Bioexcell) every other day. I.p.…”

Section: Methodsmentioning

confidence: 99%

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Opposing roles of endothelial and leukocyte-expressed IL-7Rα in the regulation of psoriasis-like skin inflammation

Vranova

Friess

Jahromi

et al. 2019

Sci Rep

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The interleukin 7 receptor alpha chain (IL-7Rα) is predominately expressed by lymphocytes, and activation by its ligand IL-7 supports the development and maintenance of T cells and boosts T-cell mediated immunity. We recently reported that lymphatic endothelial cells (LECs) in dermal lymphatics also express IL-7 and its receptor chains (IL-7Rα and CD132) and that IL-7 supports lymphatic drainage. This suggested that activation of IL-7Rα signaling in lymphatics could exert inflammation-resolving activity, by promoting the clearance of excess tissue fluid. Here we investigated how the potentially opposing effects of IL-7Rα signaling in immune cells and in the lymphatic vasculature would affect the development and progression of psoriasis-like skin inflammation. We found that during acute and chronic skin inflammation mice with an endothelial-specific deletion of IL-7Rα (IL-7Rα ΔEC mice) developed more edema compared to control mice, as a consequence of impaired lymphatic drainage. However, systemic treatment of wild-type mice with IL-7 exacerbated edema and immune cell infiltration in spite of increasing lymphatic drainage, whereas treatment with IL-7Rα blocking antibody ameliorated inflammatory symptoms. These data identify IL-7Rα signaling as a new pathway in psoriasis-like skin inflammation and show that its pro-inflammatory effects on the immune compartment override its anti-inflammatory, drainage-enhancing effects on the endothelium.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Opposing roles of endothelial and leukocyte-expressed IL-7Rα in the regulation of psoriasis-like skin inflammation

Vranova

Friess

Jahromi

et al. 2019

Sci Rep

Self Cite

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“…Compared to the control-treated mice, Treg frequencies in dLNs were significantly increased, indicating tolerance-inducing conditions [155]. Surprisingly, the beneficial effect of ALCAM blockade on corneal transplant survival could not be attributed to impaired lymph-or hemangiogenesis, since no difference was detected in vessel ingrowth into the cornea between treated and control mice.…”

Section: Activated Leukocyte Cell Adhesion Molecule (Alcam)mentioning

confidence: 87%

“…Focusing on DCs, blockade of ALCAM reduced the adhesion of DCs to LEC monolayers [152]. Studies on in vitro-cultured human skin biopsies showed reduced emigration from DCs when ALCAM was blocked [155]. However, its confirmed role in the organization and function of lymphatic vessels, together with an indicated effect on DC migration, suggests therapeutic potential.…”

Section: Activated Leukocyte Cell Adhesion Molecule (Alcam)mentioning

confidence: 99%

Immunomodulatory Strategies Targeting Dendritic Cells to Improve Corneal Graft Survival

Schönberg

Hamdorf

Bock

2020

JCM

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Even though the cornea is regarded as an immune-privileged tissue, transplantation always comes with the risk of rejection due to mismatches between donor and recipient. It is common sense that an alternative to corticosteroids as the current gold standard for treatment of corneal transplantation is needed. Since blood and lymphatic vessels have been identified as a severe risk factor for corneal allograft survival, much research has focused on vessel regression or inhibition of hem- and lymphangiogenesis in general. However, lymphatic vessels have been identified as required for the inflammation’s resolution. Therefore, targeting other players of corneal engraftment could reveal new therapeutic strategies. The establishment of a tolerogenic microenvironment at the graft site would leave the recipient with the ability to manage pathogenic conditions independent from transplantation. Dendritic cells (DCs) as the central player of the immune system represent a target that allows the induction of tolerogenic mechanisms by many different strategies. These strategies are reviewed in this article with regard to their success in corneal transplantation.

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“…(S1pr1). Alcam is required for cDC migration via afferent lymphatics, and its blockade through high-affinity antibodies induces cDC retention and alleviates cDC-induced allogenic responses (52). Further, since migratory cDCs can activate T cells through a stable immunological synapse (53), the upregulated Alcam level may explain the increase of T EM cells vs. naïve T-cell populations following pre-treatment with tRA.…”

Section: Enhancement Of Systemic Inflammation By Tra Pre-treatment Inmentioning

confidence: 99%

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus

et al. 2020

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We previously showed that all-trans-retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen, indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre-and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.

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ALCAM Mediates DC Migration Through Afferent Lymphatics and Promotes Allospecific Immune Reactions

Cited by 30 publications

References 55 publications

Opposing roles of endothelial and leukocyte-expressed IL-7Rα in the regulation of psoriasis-like skin inflammation

Opposing roles of endothelial and leukocyte-expressed IL-7Rα in the regulation of psoriasis-like skin inflammation

Immunomodulatory Strategies Targeting Dendritic Cells to Improve Corneal Graft Survival

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus

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