Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

Abstract

The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs), a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases.

Figure 1

Canonical Wnt signaling pathway (β-catenin-dependent Wnt signaling pathway). In the absence of Wnt ligand(s), cytoplasmic β-catenin is targeted for phosphorylation, by a multiprotein complex comprising Axin, adenomatous polyposis coli (APC), the glycogen synthase kinase 3β (GSK3β), and casein kinase 1α (CK1α). The phosphorylated form of β-catenin is recognized by an E3 ubiquitin ligase (β-TrCP) and then targeted to proteasomal degradation, resulting in low cytosolic levels (left panel); in the presence of Wnt ligand(s), Wnt ligand binds to the Fzd and LRP receptors, and this binding triggers the signaling and activates the Dvl; the activation of Dvl inhibits the GSK-3β and results in destructing the multiprotein complex which stabilizes and leads to the intracellular accumulation of β-catenin in the cytoplasm; accordingly the active β-catenin translocates to the nucleus, where it acts as a transcriptional coactivator with TCF/LEF to activate Wnt-responsive target genes (right panel).

Figure 2

Noncanonical Wnt signaling pathway (β-catenin-independent Wnt signaling pathway). Noncanonical Wnt ligand (such as the Wnt5a, a typical noncanonical Wnt) binds to its receptor (Fzd) and coreceptor (Ror1/2) and triggers the noncanonical signaling cascades, which includes the Wnt/Calcium (Ca²⁺) and Wnt/planar cell polarity (PCP) pathways. In the Wnt/Ca²⁺ pathway (left panel), Wnt protein binds to Fzd and Ror2 receptor and leads to activate G proteins, resulting in enhancing the intracellular calcium levels, or decreases cGMP; the calcium/calmodulin-dependent protein kinase II (CaMKII) or protein kinase C (PKC) was then activated. In the Wnt/PCP pathway (right panel), Wnt proteins bind to Fzd receptors on the cell surface followed by activating Rho/Rac small GTPase and Jun N-terminal kinase (JNK) to assist with cytoskeletal organization and gene expression.