Chinese Medical Sciences Journal ›› 2022, Vol. 37 ›› Issue (3): 265-274.doi: 10.24920/003994
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Dual Role of Wnt5a in the Progression of Inflammatory Diseases
Xu Chen1, Hongling Liu2, Dehong Li3, Jinsui Wang1, Fenghui Zhao1, *(
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- 1Department of Pathology, Gansu Provincial Hospital, Lazhou 730000, China
2Department of Occupational Medicine, the Third Gansu Provincial Hospital, Lanzhou 730000, China
3Department of Clinical Laboratory, Gansu Provincial Hospital, Lanzhou 730000, China
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Received:2021-09-09Accepted:2022-03-06Published:2022-09-30Online:2022-05-11 -
Contact:Fenghui Zhao E-mail:zhaofh0931@163.com
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Xu Chen, Hongling Liu, Dehong Li, Jinsui Wang, Fenghui Zhao. Dual Role of Wnt5a in the Progression of Inflammatory Diseases[J].Chinese Medical Sciences Journal, 2022, 37(3): 265-274.
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Figure 1.
Wnt5a-related signaling pathways. (A) Wnt/β-catenin signaling pathway. (a) In the “off” state, the frizzled protein is not bound to Wnt5a. β-catenin is phosphorylated by GSK3β/Axin/APC/CK1-α and then degraded by the ubiquitin-proteasome. (b) Wnt5a binds to the receptor Frizzled and switches the signaling pathway to the “on” state. Phosphorylation of Dvl disrupts the GSK3β/Axin/APC/CK1-α complex, which dephosphorylates β-catenin and increases its cytoplasmic accumulation. It eventually translocates to the nucleus and binds to TCF/LEF, leading to the transcription of Wnt-responsive genes. (B) Non-canonical Wnt signaling pathways. (a) Wnt-Ca2+ signaling pathway. The Wnt5a-Frizzled interaction phosphorylates Dvl, which breaks down PIP2 to IP3 and DAG. IP3 triggers Ca2+ efflux, which activates PKC, CAMK II, and calcineurin. The latter activates NFAT and the transcription of downstream target genes. Activated PKC and CAMK II inhibit the binding of β-catenin and TCF/LEF by blocking the Wnt/β-catenin signaling pathway. (b) Wnt-PCP signaling pathway. Wnt5a binds to Frizzled receptor and phosphorylates Dvl, which activates Rac and Rho, leading to JNK translocation into the nucleus and transcription of c-jun target genes."
Figure 1.
Figure 2.
The dual role of Wnt5a in the inflammatory response. (A) Antigen stimulation of macrophages and microglia activate NF-κB/COX-2 pathway via TLRs, leading to Wnt5a upregulation. Wnt5a binds to the receptor Frizzled 5 and induces IL-10 secretion, inhibiting the NF-κB inflammatory pathway. (B) Wnt5a and Frizzled 5 binding activates Ca2+ signaling, leading to IL-6, IL-8, IL-1β, IL-12, MIP-1β, MCP-1, and COX-2 secretion. (C) Wnt5a/Frizzled 5 complex stimulates T-cells to secrete CCL2, IL-8, and IFN-γ, which recruits macrophages, lymphocytes, and neutrophils. (D) Macrophage-derived Wnt5a induces aberrant proliferation, death, and metabolism in the peripheral tissues via PCP signaling."
Figure 2.
Figure 3
The role of Wnt5a in inflammatory diseases. (A) Wnt5a aggravates rheumatoid arthritis. (B) Wnt5a regulates psoriasis via bi-direction. (C) Wnt5a aggravates atherosclerosis. (D) Wnt5a regulates diabetes mellitus via bi-direction. (E) Wnt5a regulates sepsis via bi-direction. (F) Wnt5a regulates chronic obstructive pulmonary diseases via bi-direction."
Figure 3
Figure 4.
Possible mechanisms of the bidirectional role of Wnt5a in inflammatory diseases. (A) Promoter A demethylation leads to the production of Wnt5a-L, whereas promoter B demethylation predominantly results in Wnt5a-S. (B) Wnt5a-L combines with Fzd7 and inhibits NF-kB and β-catenin, stimulating the Wnt5a/Fzd7/IL-10 and Wnt5a/CAMKII/β-catenin pathways, and attenuates pro-inflammatory cytokines secretion and cell proliferation. (C) Wnt5a-S binding to Fzd5 and Ror2 stimulate the Wnt5a-CAMKII-NFAT and Wnr5a-PCP signaling, resulting in inflammatory cytokines secretion, abnormal cell proliferation and metabolism."
Figure 4.
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