Myeloid-derived Wnts play an indispensible role in macrophage and fibroblast activation and kidney fibrosis

Tian, Yuan; Chen, Jiongcheng; Huang, Wenshu; Ren, Qian; Feng, Junxia; Liao, Jinlin; Fu, Haiyan; Zhou, Lili; Liu, Youhua

doi:10.7150/ijbs.94166

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Int J Biol Sci 2024; 20(6):2310-2322. doi:10.7150/ijbs.94166 This issue Cite

Research Paper

Myeloid-derived Wnts play an indispensible role in macrophage and fibroblast activation and kidney fibrosis

Yuan Tian^1,2*, Jiongcheng Chen^1*, Wenshu Huang¹, Qian Ren¹, Junxia Feng¹, Jinlin Liao¹, Haiyan Fu^1,3, Lili Zhou^1,3✉, Youhua Liu^1,3✉

1. State Key Laboratory of Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
2. Department of Nephrology, Jingzhou Hospital Affiliated to Yangze University, Jingzhou, China.
3. National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China.
*Equal contribution.

Citation:

Tian Y, Chen J, Huang W, Ren Q, Feng J, Liao J, Fu H, Zhou L, Liu Y. Myeloid-derived Wnts play an indispensible role in macrophage and fibroblast activation and kidney fibrosis. Int J Biol Sci 2024; 20(6):2310-2322. doi:10.7150/ijbs.94166. https://www.ijbs.com/v20p2310.htm

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Abstract

Wnt/β-catenin signaling plays a pivotal role in the pathogenesis of chronic kidney diseases (CKD), which is associated with macrophage activation and polarization. However, the relative contribution of macrophage-derived Wnts in the evolution of CKD is poorly understood. Here we demonstrate a critical role of Wnts secreted by macrophages in regulating renal inflammation and fibrosis after various injuries. In mouse model of kidney fibrosis induced by unilateral ureteral obstruction (UUO), macrophages were activated and polarized to M1 and M2 subtypes, which coincided with the activation of Wnt/β-catenin signaling. In vitro, multiple Wnts were induced in primary cultured bone marrow-derived macrophages (BMDMs) after polarization. Conversely, Wnt proteins also stimulated the activation and polarization of BMDMs to M1 and M2 subtype. Blockade of Wnt secretion from macrophages in mice with myeloid-specific ablation of Wntless (Wls), a cargo receptor that is obligatory for Wnt trafficking and secretion, blunted macrophage infiltration and activation and inhibited the expression of inflammatory cytokines. Inhibition of Wnt secretion by macrophages also abolished β-catenin activation in tubular epithelium, repressed myofibroblast activation and reduced kidney fibrosis after either obstructive or ischemic injury. Furthermore, conditioned medium from Wls-deficient BMDMs exhibited less potency to stimulate fibroblast proliferation and activation, compared to the controls. These results underscore an indispensable role of macrophage-derived Wnts in promoting renal inflammation, fibroblasts activation and kidney fibrosis.

Keywords: Macrophage, Wnt, Wntless, fibroblast activation, kidney fibrosis

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APA

Tian, Y., Chen, J., Huang, W., Ren, Q., Feng, J., Liao, J., Fu, H., Zhou, L., Liu, Y. (2024). Myeloid-derived Wnts play an indispensible role in macrophage and fibroblast activation and kidney fibrosis. International Journal of Biological Sciences, 20(6), 2310-2322. https://doi.org/10.7150/ijbs.94166.

ACS

Tian, Y.; Chen, J.; Huang, W.; Ren, Q.; Feng, J.; Liao, J.; Fu, H.; Zhou, L.; Liu, Y. Myeloid-derived Wnts play an indispensible role in macrophage and fibroblast activation and kidney fibrosis. Int. J. Biol. Sci. 2024, 20 (6), 2310-2322. DOI: 10.7150/ijbs.94166.

NLM

CSE

Tian Y, Chen J, Huang W, Ren Q, Feng J, Liao J, Fu H, Zhou L, Liu Y. 2024. Myeloid-derived Wnts play an indispensible role in macrophage and fibroblast activation and kidney fibrosis. Int J Biol Sci. 20(6):2310-2322.

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