The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation

Chae, Wook Jin; Ehrlich, Allison; Chan, Pamela; Teixeira, Alexandra M.; Henegariu, Octavian; Hao, Liming; Shin, Jae Hun; Park, Jong Hyun; Tang, Wai Ho; Kim, Sang Taek; Maher, Stephen E.; Goldsmith-Pestana, Karen; Shan, Peiying; Hwa, John; Lee, Patricia; Krause, Diane S.; Rothlin, Carla V.; McMahon-Pratt, Diane; Bothwell, Alfred L.M.

doi:10.1016/j.immuni.2016.01.008

Cited by 110 publications

(114 citation statements)

References 66 publications

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“…Previous studies demonstrated thrombocytes (or platelets) or cancer cells as sources of DKK‐1 upon exposure to external stimuli (e.g. parasites or allergens) or alterations in cancerous cells . Notably, membrane‐bound TGF‐ β is also highly expressed in thrombocytes and Treg cells similar to DKK‐1 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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SummaryInduction of tolerance is a key mechanism to maintain or to restore immunological homeostasis. Here we show that Foxp3+ regulatory T (Treg) cells use Dickkopf‐1 (DKK‐1) to regulate T‐cell‐mediated tolerance in the T‐cell‐mediated autoimmune colitis model. Treg cells from DKK‐1 hypomorphic doubleridge mice failed to control CD4+ T‐cell proliferation, resulting in CD4 T‐cell‐mediated autoimmune colitis. Thymus‐derived Treg cells showed a robust expression of DKK‐1 but not in naive or effector CD4 T cells. DKK‐1 expression in Foxp3+ Treg cells was further increased upon T‐cell receptor stimulation in vitro and in vivo. Interestingly, Foxp3+ Treg cells expressed DKK‐1 in the cell membrane and the functional inhibition of DKK‐1 using DKK‐1 monoclonal antibody abrogated the suppressor function of Foxp3+ Treg cells. DKK‐1 expression was dependent on de novo protein synthesis and regulated by the mitogen‐activated protein kinase pathway but not by the canonical Wnt pathway. Taken together, our results highlight membrane‐bound DKK‐1 as a novel Treg‐derived mediator to maintain immunological tolerance in T‐cell‐mediated autoimmune colitis.

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Section: Discussionmentioning

confidence: 99%

“…We observed that the gene expression of IL‐2‐mediated signalling inhibitory protein Suppressor of Cytokine Signalling‐1 was increased by DKK‐1 (data not shown). DKK‐1 may inhibit Th1 cell differentiation since our previous study showed that DKK‐1 antagonizes the expression of interferon‐ γ expression by increasing Gata‐3 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Given that Wnt5a supports a proinflammatory cytokine signature (46), its potential for protection against parasite infection may also involve prevention of the predominantly Th2 signature that sustains infection (1). Recently, high serum levels of the Wnt antagonist Dkk1 have been correlated with a predominantly Th2 phenotype during the onset of experimental cutaneous leishmaniasis (47). Although cutaneous leishmaniasis and visceral leishmaniasis follow different disease courses, the overall negative correlation between Wnt signaling and infection supports the relevance of Wnt signaling in host defense against parasite infections.…”

Section: Discussionmentioning

confidence: 99%

Wnt5a Signaling Promotes Host Defense against Leishmania donovani Infection

Chakraborty

Kurati

Mahata

et al. 2017

The Journal of Immunology

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Leishmania donovani infects macrophages, disrupting immune homeostasis. The underlying mechanism that sustains infection remains unresolved. In view of the potential of Wnt5a signaling to support immune homeostasis, we evaluated the interrelationship of Wnt5a signaling and Leishmania donovani infection. Upon infecting macrophages separately with antimony drug–sensitive and –resistant L. donovani, we noted disruption in the steady-state level of Wnt5a. Moreover, inhibition of Wnt5a signaling by small interfering RNA transfection in vitro or by use of inhibitor of Wnt production in vivo led to an increase in cellular parasite load. In contrast, treatment of macrophages with recombinant Wnt5a caused a decrease in the load of antimony-sensitive and -resistant parasites, thus confirming that Wnt5a signaling antagonizes L. donovani infection. Using inhibitors of the Wnt5a signaling intermediates Rac1 and Rho kinase, we demonstrated that Wnt5a-mediated inhibition of parasite infection in macrophages is Rac1/Rho dependent. Furthermore, phalloidin staining and reactive oxygen species estimation of Wnt5a-treated macrophages suggested that a Wnt5a-Rac/Rho–mediated decrease in parasite load is associated with an increase in F- actin assembly and NADPH oxidase activity. Moreover, live microscopy of L. donovani–infected macrophages treated with Wnt5a demonstrated increased endosomal/lysosomal fusions with parasite-containing vacuoles (parasitophorous vacuoles [PV]). An increase in PV–endosomal/lysosomal fusion accompanied by augmented PV degradation in Wnt5a-treated macrophages was also apparent from transmission electron microscopy of infected cells. Our results suggest that, although L. donovani evades host immune response, at least in part through inhibition of Wnt5a signaling, revamping Wnt5a signaling can inhibit L. donovani infection, irrespective of drug sensitivity or resistance.

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“…Wnt signaling, which is implicated in T H 2-mediated inflammation 23 and T reg cell survival and function 24,25 , was significantly underrepresented in gene sets from LKB1-deficient T reg cells (Extended Data Fig. 10a).…”

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Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling

Yang

Blanco

Neale

et al. 2017

Nature

151

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Regulatory T cells (Treg cells) play a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis1,2. Transcriptional programming of regulatory mechanisms facilitates Treg cell functional activation in the prevention of diverse types of inflammatory responses3,4. How Treg cells orchestrate their homeostasis and interplay with environmental signals remains poorly understood. Here we show that liver kinase B1 (LKB1) programs proper metabolic and functional fitness of Treg cells in the control of immune tolerance and homeostasis. Mice with Treg-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive TH2-dominant responses. LKB1 deficiency disrupted Treg cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1, and TNF receptor (TNRF) superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in Treg cells was independent of conventional AMPK signaling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signaling for the proper control of PD-1 and TNFR proteins. Blockade of PD-1 activity reinvigorated the suppressive capability of LKB1-deficient Treg cells in the repression of TH2 responses and the interplay with thymic stromal lymphopoietin (TSLP)-primed dendritic cells (DCs). Thus, Treg cells employ LKB1 signaling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance.

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The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation

Cited by 110 publications

References 66 publications

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

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

Wnt5a Signaling Promotes Host Defense against Leishmania donovani Infection

Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling

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The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation

Cited by 110 publications

References 66 publications

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

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

Wnt5a Signaling Promotes Host Defense against Leishmania donovani Infection

Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling

Contact Info

Product

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

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