The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation

Abstract

IntroductionImmunity to infections depends on the successful integration of innate and adaptive defense strategies. 1 Cells of the innate immune system, such as macrophages and dendritic cells, recognize pathogen-associated molecular patterns shared by many microbes but not found in higher eukaryotes, via members of the Toll-like receptor (TLR) family. 2,3 TLR-dependent signaling pathways can directly induce macrophage antimicrobial programs but also initiate inflammatory cell recruitment and help prime cells of the adaptive immune system to amplify bactericidal effector mechanisms. Experimental infections with microorganisms have been used successfully to uncover the intricacies governing the interplay between innate and adaptive immunity. 4,5 For example, cell-wall components of Mycobacterium tuberculosis, the causative organism of tuberculosis, critically depend on TLR2 and TLR4 to induce secretion of the proinflammatory cytokines tumor necrosis factor alpha (TNF-␣) and interleukin (IL-12, necessary for differentiating T-helper 1 cells). 6 Subsequently, mycobacteria-primed T cells secrete interferon gamma (IFN-␥) as a critical macrophageactivating agent. Eradication of mycobacteria is achieved only when both arms of the immune system are fine-tuned for full antimicrobial potency.Functionally, the Toll-mediated induction of antimicrobial effector systems is highly conserved between Drosophila melanogaster (D melanogaster) and Homo sapiens. 7,8 Another example for human evolutionarily ancient effector mechanisms is granulysin (a granule-stored bactericidal molecule), which is homologous to the amoebapores of Entamoeba histolytica. 9,10 Thus, there is ample precedence for evolutionarily conserved signatures governing individual facets of the immune response. To uncover novel regulatory pathways in innate responses to infection, we performed a microarray-based gene-expression screen with human macrophages infected with mycobacteria or conserved bacterial structures. We found mRNA for WNT5A, a homolog of Wingless in Drosophila species, to be consistently up-regulated in response to all stimuli.Wingless was originally characterized as a segment polarity gene in D melanogaster, which is essential in embryonic segmentation and patterning (reviewed in Klingensmith and Nusse 11 ). Various homologs of the Wingless protein, termed WNT, are involved in embryonic development of nonvertebrates and vertebrates, 12,13 where WNT signaling determines cell motility, differentiation, and apoptosis. 14 In mammalian hematopoiesis, WNT signaling is essential for stem-cell homeostasis 15 and lymphocyte differentiation. 16,17 Most recently, one member of the WNT family of proteins, WntD, was shown to be involved in regulating antibacterial defenses in Drosophila. 18 To date, however, WNT Center Borstel, Germany), phorbol-12-myristate13-acetate (PMA), calcium ionophore A23187 (both Sigma Aldrich, Taufkirchen, Germany), and phytohemagglutinin (PHA) were used for stimulation. To rule out the presence of lipopolysaccharides (LPSs) in the...

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

“…There is strong experimental evidence for the contribution of endogenous Wnt proteins to inflammatory cytokine responses and host defense against pathogens in in vivo models [5,11,20] as well as in a variety of cell culture systems [2,6,13,14,36]. In a model of dietinduced metabolic dysfunction, sFRP5 exerted anti-inflammatory functions in vivo, possibly by interfering with Wnt5a-induced proinflammatory cytokine production [11].…”

“…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].…”

“…The 19 mammalian homologues have distinct expression patterns in embryonic and adult tissues and their 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].…”

“…Clinical associations of elevated Wnt expression and pathway activity with infections [2,3,6] and chronic inflammatory diseases [8,9,11] have sparked significant interest in elucidating immune-related functions of Wnt signaling. There is strong experimental evidence for the contribution of endogenous Wnt proteins to inflammatory cytokine responses and host defense against pathogens in in vivo models [5,11,20] as well as in a variety of cell culture systems [2,6,13,14,36]. In a model of dietinduced metabolic dysfunction, sFRP5 exerted anti-inflammatory functions in vivo, possibly by interfering with Wnt5a-induced proinflammatory cytokine production [11].…”

Atherosclerotic Calcification: Wnt Is the Hint

“…Through the calcium‐dependent Wnt signaling pathway, Wnt5a is thought to activate histone methyltransferase SET domain bifurcated 1, leading to the formation of a corepressor complex that suppresses peroxisome proliferator‐activated receptor γ (PPARγ) function and thus mediates the osteoblastic differentiation of mesenchymal stem cells (MSCs) 123. A recent study has demonstrated a link between Wnt5a, toll‐like receptor 4, and pathological inflammation in human macrophages 124. Furthermore, the expression of Wnt5a has been demonstrated in murine and human atherosclerotic tissue 19.…”