Membrane‐bound Dickkopf‐1 in Foxp3<sup>+</sup> regulatory T cells suppresses T‐cell‐mediated autoimmune colitis

Chae, Wook‐Jin; Park, Jong‐Hyun; Henegariu, Octavian; Yılmaz, Selim; Hao, Liming; Bothwell, Alfred L.M.

doi:10.1111/imm.12766

Cited by 19 publications

(25 citation statements)

References 35 publications

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“…2 inflammation (33). Recently, it was demonstrated that Dkk-1 is uniquely expressed in Foxp3 + Treg cells to inhibit T-cell-mediated autoimmune colitis as a membrane-bound form (34). However, despite the eminent role of osteocyte derived Dkk-1 on inflammation, the exact mechanism of the immunomodulatory property of Dkk-1 deserves further investigations.…”

Section: Discussionmentioning

confidence: 99%

Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis

et al. 2019

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Background: Periodontitis is a highly prevalent infection-triggered inflammatory disease that results in bone loss. Inflammation causes bone resorption by osteoclasts, and also by suppression of bone formation via increase of Dickkopf-1 (Dkk-1), an inhibitor of Wnt signaling. Here, we tested the hypothesis that osteocytic Dkk-1 is a key factor in the pathogenesis of periodontitis-induced alveolar bone loss (ABL). Methods: Twelve-week-old female mice with a constitutive deletion of Dkk-1 specifically in osteocytes (Dkk-1 fl/fl ;Dmp1:Cre) were subjected to experimental periodontitis (EP). Cre-negative littermates served as controls. EP was induced by placing a ligature around the upper 2nd left molar, the contralateral side was used as control. Mice were killed after 11 days and maxillae removed for micro-CT and histological analyses. The mRNA expression of Dkk-1, Runx2, Osteocalcin, OPG, RANKL, RANKL/OPG ratio, LEF-1, and TCF-7 were assessed in maxillae, while mRNA expressions of TNF and IL-1 were evaluated on gingiva using real-time PCR. Blood samples were collected for Dkk-1, CTX, and P1NP measurement by ELISA. Results: The deletion of Dkk-1 in osteocytes prevented ABL in mice with EP, compared to Cre-negative control mice with EP. Micro-CT analysis showed a significant reduction of bone loss (−28.5%) in EP Dkk-1 fl/fl ;Dmp1:Cre-positive mice compared to their littermate controls. These mice showed a greater alveolar bone volume, bone mineral density, trabecular number, and trabecular thickness after EP when compared to the Cre-negative controls. The local expression in maxillae as well as the serum levels of Dkk-1 were reduced in Dkk-1 fl/fl ;Dmp1:Cre-positive mice with EP. The transgenic mice submitted to EP showed increase of P1NP and reduction of CTX-I serum levels, and increase of TCF-7 expression. Histological analysis displayed less inflammatory infiltrates, a reduction of TNF and IL-1 expressions in the gingiva and fewer osteoclasts in Cre-positive animals with EP. Moreover, in mice with EP, the osteocytic deletion of Dkk-1 enhanced bone formation due to increased expressions of Runx2 and Osteocalcin and decreased expression of RANKL in maxillae. Conclusion: In summary, Dkk-1 derived from osteocytes plays a crucial role in ABL in periodontitis.

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Section: Discussionmentioning

confidence: 99%

Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis

et al. 2019

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“…Whether DKK-3 could modulate Wnt signaling was not addressed in this study. For DKK-1, the expression of this protein in regulatory T cells was demonstrated in a murine IBD model with a lymphopenic environment, suggesting that DKK-1 harbors an immunosuppressive role in Tregs, and prevents CD4 + T cell proliferation [92]. The study also showed that DKK-1 expression was independent of Wnt pathway activation.…”

Section: Wnt Antagonists and Inflammatory Diseases Dkk Family Membersmentioning

confidence: 76%

Canonical and Non-Canonical Wnt Signaling in Immune Cells

Chae

Bothwell

2018

Trends in Immunology

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128

111

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Cell differentiation, proliferation, and death are vital for immune homeostasis. Wnt signaling plays essential roles in processes across species. The roles of Wnt signaling proteins and Wnt ligands have been studied in the past, but the context-dependent mechanisms and functions of these pathways in immune responses remain unclear. Recent findings regarding the role of Wnt ligands and Wnt signaling in immune cells and their immunomodulatory mechanisms suggest that Wnt ligands and signaling are significant in regulating immune responses. We introduce recent key findings and future perspectives on Wnt ligands and their signaling pathways in immune cells as well as the immunological roles and functions of Wnt antagonists.

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“…However, another study showed that at least canonical Wnt signaling had a negative effect on Treg function (53). The positive association of membrane-bound DKK-1, a Wnt antagonist, and the suppressive function of Tregs confirmed this observation (54). Analyzing the proportion of CD25 + /Foxp3 + Tregs among the CD4 + effector T cells, we did not detect any effect of either Wnt-1 or Wnt-5a in the lung or draining lymph node, consistent with our transgenic assay data.…”

Section: Discussionmentioning

confidence: 87%

The Canonical but Not the Noncanonical Wnt Pathway Inhibits the Development of Allergic Airway Disease

Beckert

Meyer-Martin

Buhl

et al. 2018

The Journal of Immunology

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Asthma is a syndrome with multifactorial causes, resulting in a variety of different phenotypes. Current treatment options are not curative and are sometimes ineffective in certain disease phenotypes. Therefore, novel therapeutic approaches are required. Recent findings have shown that activation of the canonical Wnt signaling pathway suppresses the development of allergic airway disease. In contrast, the effect of the noncanonical Wnt signaling pathway activation on allergic airway disease is not well described. The aim of this study was to validate the therapeutic effectiveness of Wnt-1-driven canonical Wnt signaling compared with Wnt-5a-driven noncanonical signaling in murine models. In vitro, both ligands were capable of attenuating allergen-specific T cell activation in a dendritic cell-dependent manner. In addition, the therapeutic effects of Wnt ligands were assessed in two different models of allergic airway disease. Application of Wnt-1 resulted in suppression of airway inflammation as well as airway hyperresponsiveness and mucus production. In contrast, administration of Wnt-5a was less effective in reducing airway inflammation or goblet cell metaplasia. These results suggest an immune modulating function for canonical as well as noncanonical Wnt signaling, but canonical Wnt pathway activation appears to be more effective in suppressing allergic airway disease than noncanonical Wnt activation.

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Membrane‐bound Dickkopf‐1 in Foxp3⁺ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis

Cited by 19 publications

References 35 publications

Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis

Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis

Canonical and Non-Canonical Wnt Signaling in Immune Cells

The Canonical but Not the Noncanonical Wnt Pathway Inhibits the Development of Allergic Airway Disease

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Membrane‐bound Dickkopf‐1 in Foxp3+ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis

Cited by 19 publications

References 35 publications

Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis

Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis

Canonical and Non-Canonical Wnt Signaling in Immune Cells

The Canonical but Not the Noncanonical Wnt Pathway Inhibits the Development of Allergic Airway Disease

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Membrane‐bound Dickkopf‐1 in Foxp3⁺ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis