Wnt signaling in macrophages: Augmenting and inhibiting mycobacteria-induced inflammatory responses

Schaale, Kolja; Neumann, J; Schneider, Dagmar; Ehlers, Stefan; Reiling, Norbert

doi:10.1016/j.ejcb.2010.11.004

Cited by 154 publications

(158 citation statements)

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“…Depending on the receptor availability, Wnt5a can activate or inhibit the canonical Wnt signaling pathway (57). Moreover, Wnt5a has recently emerged as a macrophage effector molecule that triggers inflammation (58,59). Another protein whose knockdown reduced the infection highly significantly at 1 day p.i.…”

Section: Discussionmentioning

confidence: 99%

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

et al. 2016

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Ehrlichia chaffeensis invades and survives in phagocytes by modulating host cell processes and evading innate defenses, but the mechanisms are not fully defined. Recently we have determined that E. chaffeensis tandem repeat proteins (TRPs) are type 1 secreted effectors involved in functionally diverse interactions with host targets, including components of the evolutionarily conserved Wnt signaling pathways. In this study, we demonstrated that induction of host canonical and noncanonical Wnt pathways by E. chaffeensis TRP effectors stimulates phagocytosis and promotes intracellular survival. After E. chaffeensis infection, canonical and noncanonical Wnt signalings were significantly stimulated during early stages of infection (1 to 3 h) which coincided with dephosphorylation and nuclear translocation of ␤-catenin, a major canonical Wnt signal transducer, and NFATC1, a noncanonical Wnt transcription factor. In total, the expression of ϳ44% of Wnt signaling target genes was altered during infec- Ehrlichia chaffeensis is an obligately intracellular bacterium responsible for the emerging life-threatening human zoonosis human monocytotropic ehrlichiosis (HME) (1). E. chaffeensis selectively infects mononuclear phagocytes and resides in early-endosome-like membrane-bound vacuoles (1). The mechanisms by which E. chaffeensis enters host cells, establishes persistent infection, and avoids host defenses are not completely understood but occur through functionally relevant host-pathogen interactions involving secreted ehrlichial tandem repeat protein (TRP) effectors that are posttranslationally modified by ubiquitin (Ub) and the small ubiquitin-like modifier (SUMO) (2-5). E. chaffeensis TRPs interact with a diverse group of human proteins associated with major cellular processes, including transcription, translation, protein trafficking, cell signaling, cytoskeleton organization, and apoptosis, indicating that they play a role in manipulating these important cellular processes to facilitate infection (6-8).E. chaffeensis TRPs were first recognized as antigens that elicit strong protective antibody responses during infection that are directed at continuous species-specific epitopes in tandem repeat regions (9-12). Subsequently, our understanding of the functional role of TRPs as effectors in pathobiology has been advanced through studies that have defined specific TRP-host protein and DNA interactions (4, 13). Notably, E. chaffeensis TRP120 and TRP32 interact with numerous host proteins and genes associated with the canonical and noncanonical Wnt signaling pathways. One of TRP32-interacting targets, deleted-in-azoospermia-associated protein 2 (DAZAP2), is a highly conserved protein that modulates gene transcription driven by Wnt/␤-catenin signaling effector T-cell factors (TCFs), and knockdown of host DAZAP2 by small interfering RNA (siRNA) reduced the E. chaffeensis load in infected cells (7,14). Several other TRP120-interacting host proteins, such as AT-rich interactive domain 1B (ARID1B), lysine (K)-specific demethylase...

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Section: Discussionmentioning

confidence: 99%

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

et al. 2016

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“…In addition, in macrophages, which are modulators rather than initiators of adaptive immunity, Wnt/␤-catenin signaling confers an anti-inflammatory phenotype to the cells, 35 further establishing this pathway as a potential therapeutic target in inflammatory diseases. In macrophages, however, the E-cadherin/catenin complex has mainly been studied as adhesive moiety, enabling these cells to fuse or to interact with E-cadherin-, KLRG1-, and ␣ E (CD103)␤ 7 integrin-expressing cells.…”

Section: Future Perspectives and Potential Clinical Implicationsmentioning

confidence: 99%

“…32 However, unbound E-cadherin might also stimulate Wnt/␤-catenin signaling by assembling the Wnt signalosome, which phosphorylates E-cadherin and then releases ␤-catenin in the cytoplasm. 34 Interestingly, ␤-catenin functioning has been shown to instruct anti-inflammatory macrophages 35 and tolerogenic DCs. 36,37 (B) E-cadherin modulates PI3K/Akt signaling.…”

Section: E-cadherin Modulates Rho-family Gtpase Activitymentioning

confidence: 99%

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Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

Bossche

Malissen

Mantovani

et al. 2012

Blood

140

121

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E-cadherin is best characterized as adherens junction protein, which through homotypic interactions contributes to the maintenance of the epithelial barrier function. In epithelial cells, the cytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellular signal transduction pathways, including Wnt/␤-catenin, PI3K/Akt, Rho GTPase, and NF-B signaling. Recent progress uncovered a novel and critical role for this adhesion molecule in mononuclear phagocyte functions. Ecadherin regulates the maturation and migration of Langerhans cells, and its ligation prevents the induction of a tolerogenic state in bone marrow-derived dendritic cells (DCs). In this respect, the functionality of ␤-catenin could be instrumental in determining the balance between immunogenicity and tolerogenicity of DCs in vitro and in vivo. Fusion of alternatively activated macrophages and osteoclasts is also Ecadherin-dependent. In addition, the Ecadherin ligands CD103 and KLRG1 are expressed on DC-, T-, and NK-cell subsets and contribute to their interaction with E-cadherin-expressing DCs and macrophages. Here we discuss the regulation, function, and implications of Ecadherin expression in these central orchestrators of the immune system. (Blood. 2012;119(7):1623-1633) IntroductionCadherins are transmembrane or membrane-associated glycoproteins that mediate Ca 2ϩ -dependent cell-cell adhesion and have mainly been described for their instrumental role during morphogenesis of a variety of organs. 1 The cadherin superfamily composes classic type I cadherins, closely related type II cadherins, desmosomal cadherins, protocadherins, and several cadherin-related molecules. Cadherin-1 (encoded by Cdh1), also known as CD324, uvomorulin, or E-cadherin, in which the "E" stands for "epithelial," is the founding member of the classic type I cadherin family, which also includes N-cadherin (neural, Cdh2), P-cadherin (placental, Cdh3), Cdh4), and VE-cadherin (vascular endothelial, Cdh5). For several decades, E-cadherin has been known as a major constituent of adherens junctions (AJs), mediating strong homotypic adhesion between neighboring epithelial cells, thereby safeguarding epithelial barrier integrity. 2 The lack of functional tight junction and desmosome formation in the absence of E-cadherin emphasizes its central role in the regulation of epithelial cell-cell contacts. 3 Cell-cell adhesion is mainly executed by the formation of E-cadherin trans-homodimers. Indeed, the E-cadherin molecule contains an ectodomain composed of 5 extracellular cadherin (EC1-5) repeats (550 aa in total), in which EC1 composes the HAV peptide sequence responsible for homophilic interactions, a transmembrane region, and a cytoplasmic tail (150 aa). 2 The latter can be further subdivided into a ␤-catenin binding domain and a membrane proximal cytoplasmic/conserved domain, whose core sequence motif DEEGGGEED is important for p120-catenin binding, resulting in the stabilization of the E-cadherin/catenin complex at the cell surface. 4 E-cadhe...

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“…CCL2 and CCL5) by macrophages and other cell types [2,6,11,13,14]. Wnt proteins, such as Wnt5a, which signal via β-Catenin-independent pathways, including Ca 2+ mobilization, NF-κB, and MAP kinase activation, have been proposed to amplify local inflammation [15,16]. In contrast, Wnt proteins that stabilize the transcriptional co-activator β-Catenin, such as Wnt3a, are thought to have anti-inflammatory roles, e.g.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll‐like receptor 4

Nguyen

Irvine

et al. 2014

Eur J Immunol

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An increasing number of studies address the roles of Wnt proteins in shaping leukocyte functions. Recombinant Wnt3a and Wnt5a, prototypical activators of β-Catenindependent and -independent Wnt signaling, respectively, are widely used to investigate the effects of Wnt proteins on myeloid cell functions. Recent reports describe both proinflammatory and immunemodulatory effects of Wnt3a and Wnt5a on macrophages, DCs, and microglia. The underlying molecular mechanisms for this divergence are unclear. We show here that recombinant Wnt3a-and Wnt5a-induced cytokine production from murine C57BL/6 macrophages was dependent on TLR4 and inhibited by Polymyxin B. Similarly, impairment of TLR-induced cytokine production upon preexposure to Wnt proteins was TLR4 dependent. The extent of Wnt3a-and Wnt5a-induced inflammatory gene expression greatly varied between Wnt protein lots. We conclude that cytokine responses and TLR tolerization induced by recombinant Wnt proteins are likely explained by contaminating TLR4 agonists, although we cannot fully exclude that Wnt proteins have an intrinsic capacity to signal via TLR4. This study emphasizes the need for careful, independent verification of Wnt-mediated cellular responses. Keywords: Cytokines r Macrophages r TLR r Wnt proteinsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionWnt proteins are secreted regulators of cellular proliferation and differentiation. The 19 mammalian homologues have distinct expression patterns in embryonic and adult tissues and their Correspondence: Dr. Antje Blumenthal e-mail: a.blumenthal@uq.edu.au functions in embryogenesis and tissue homeostasis have been widely studied [1]. Recent associations of increased Wnt expression with bacterial infections and chronic inflammation in patients and model systems have created considerable interest in immunerelated Wnt functions. Elevated Wnt expression has been reported * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 1480-1490 Innate immunity 1481 during infections with mycobacteria, Gram-negative and Grampositive bacteria [2][3][4][5][6], and chronic inflammation in rheumatoid arthritis, atherosclerosis, obesity, and psoriasis [7][8][9][10][11][12]. Inflammatory cytokines and chemokines are common drivers of these diverse pathologies. Endogenous Wnt proteins, in particular Wnt5a, have been shown to induce and enhance the production of inflammatory cytokines (e.g. IL-12 and IL-6) and chemokines (e.g. CCL2 and CCL5) by macrophages and other cell types [2,6,11,13,14]. Wnt proteins, such as Wnt5a, which signal via β-Catenin-independent pathways, including Ca 2+ mobilization, NF-κB, and MAP kinase activation, have been proposed to amplify local inflammation [15,16]. In contrast, Wnt proteins that stabilize the transcriptional co-activator β-Catenin, such as Wnt3a, are thought to have anti-inflammatory roles, e.g. suppression of cytokine expressi...

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Wnt signaling in macrophages: Augmenting and inhibiting mycobacteria-induced inflammatory responses

Cited by 154 publications

References 64 publications

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll‐like receptor 4

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