Clec7a-KO Mouse

Clec7a, also known as Dectin-1, is a pattern recognition receptor involved in fungal recognition and innate immune responses. It activates the SYK signaling pathway and is associated with various biological processes such as phagocytosis, inflammation, and lipid metabolism [1,2,3,5,8].

In an ischemic stroke mouse model, Clec7a in microglia was found to play a critical role in mediating synaptic phagocytosis, worsening long-term outcomes. Manipulating its expression could regulate microglial phagocytosis of synapses, potentially improving neurobehavioral outcomes [1]. In a mouse renal ischemia/reperfusion injury model for acute kidney injury, Clec7a was crucial for the fine regulation of macrophage phenotype. The combined expression of Clec7a in M1 macrophages and its depletion in M2 macrophages significantly improved renal function [2]. In high-fat diet-fed mice, Clec7a was highly expressed and its agonist accelerated diet-induced obesity, while Clec7a deficiency in mice resulted in resistance to diet-induced obesity [3]. In gliomas, its up-regulation was associated with tumor malignancy and it influenced macrophage function [4]. In Alzheimer's disease mouse models, systemic administration of an antibody against CLEC7A rescued microglia activation in mice expressing the TREM2R47H allele [5]. In an ischemic stroke model established by middle cerebral artery occlusion and reperfusion, CLEC7A knockdown alleviated the condition by inhibiting pyroptosis and microglial activation [6]. In a neuropathic pain model, l-THP alleviated pain by inhibiting the activation of the Clec7a-MAPK/NF-κB-NLRP3 inflammasome axis, and Clec7a overexpression partly eliminated the analgesic effect of l-THP [7]. In patients with disseminated coccidioidomycosis, damaging CLEC7A variants were associated with impaired production of β-glucan-stimulated TNF-α [8]. In a Parkinson's disease rat model, AAV-mediated specific knockdown of Clec7a in microglial alleviated motor deficits and dopaminergic neuron damage, restraining neuroinflammation [9]. In transgenic AD-model mice, conditional targeting of MGnD microglia by miR-155 ablation diminished retinal Clec7a+ microglial populations, protecting the inner blood-retina barrier and reducing vascular amyloidosis [10].

In conclusion, Clec7a is involved in multiple biological processes and plays important roles in various disease conditions, including ischemic stroke, acute kidney injury, obesity, gliomas, Alzheimer's disease, neuropathic pain, disseminated coccidioidomycosis, Parkinson's disease, and Alzheimer's-induced retinal vasculopathy. Gene knockout or knockdown models in mice have significantly contributed to revealing the functions of Clec7a in these diseases, providing potential therapeutic targets.

References:

1. Wan, Hanxi, He, Mengfan, Cheng, Chun, Tian, Li, Xiong, Lize. 2024. Clec7a Worsens Long-Term Outcomes after Ischemic Stroke by Aggravating Microglia-Mediated Synapse Elimination. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2403064. doi:10.1002/advs.202403064. https://pubmed.ncbi.nlm.nih.gov/39088351/

2. Wang, Yaqiong, Li, Xianzhe, Xu, Xialian, Shen, Bo, Ding, Xiaoqiang. 2022. Clec7a expression in inflammatory macrophages orchestrates progression of acute kidney injury. In Frontiers in immunology, 13, 1008727. doi:10.3389/fimmu.2022.1008727. https://pubmed.ncbi.nlm.nih.gov/36189317/

3. Ma, Jie, Zhou, Miao, Song, Zehe, Yin, Yulong, Yin, Jie. 2023. Clec7a drives gut fungus-mediated host lipid deposition. In Microbiome, 11, 264. doi:10.1186/s40168-023-01698-5. https://pubmed.ncbi.nlm.nih.gov/38007451/

4. Wang, Jinchao, Li, Xiaoru, Wang, Kai, Xu, Shangchen, Zhang, Jianning. 2024. CLEC7A regulates M2 macrophages to suppress the immune microenvironment and implies poorer prognosis of glioma. In Frontiers in immunology, 15, 1361351. doi:10.3389/fimmu.2024.1361351. https://pubmed.ncbi.nlm.nih.gov/38846954/

5. Wang, Shoutang, Sudan, Raki, Peng, Vincent, Brioschi, Simone, Colonna, Marco. . TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways. In Cell, 185, 4153-4169.e19. doi:10.1016/j.cell.2022.09.033. https://pubmed.ncbi.nlm.nih.gov/36306735/

6. Li, Wei, Feng, Xiaoli, Zhang, Manyu, Zhao, Zhenqiang, Xia, Min. . CLEC7A Knockdown Alleviates Ischemic Stroke by Inhibiting Pyroptosis and Microglia Activation. In Journal of integrative neuroscience, 23, 219. doi:10.31083/j.jin2312219. https://pubmed.ncbi.nlm.nih.gov/39735961/

7. Wu, Dan, Wang, Ping, Zhao, Chunhui, Zhang, Yanqiong, Xu, Haiyu. 2023. Levo-tetrahydropalmatine ameliorates neuropathic pain by inhibiting the activation of the Clec7a-MAPK/NF-κB-NLRP3 inflammasome axis. In Phytomedicine : international journal of phytotherapy and phytopharmacology, 121, 155075. doi:10.1016/j.phymed.2023.155075. https://pubmed.ncbi.nlm.nih.gov/37741158/

8. Hsu, Amy P, Korzeniowska, Agnieszka, Aguilar, Cynthia C, Lionakis, Michail S, Holland, Steven M. 2022. Immunogenetics associated with severe coccidioidomycosis. In JCI insight, 7, . doi:10.1172/jci.insight.159491. https://pubmed.ncbi.nlm.nih.gov/36166305/

9. Chen, Xue-Yun, Feng, Si-Ning, Bao, Yin, Zhou, Yu-Xin, Ba, Fang. 2023. Identification of Clec7a as the therapeutic target of rTMS in alleviating Parkinson's disease: targeting neuroinflammation. In Biochimica et biophysica acta. Molecular basis of disease, 1869, 166814. doi:10.1016/j.bbadis.2023.166814. https://pubmed.ncbi.nlm.nih.gov/37495085/

10. Shi, Haoshen, Yin, Zhuoran, Koronyo, Yosef, Butovsky, Oleg, Koronyo-Hamaoui, Maya. 2022. Regulating microglial miR-155 transcriptional phenotype alleviates Alzheimer's-induced retinal vasculopathy by limiting Clec7a/Galectin-3+ neurodegenerative microglia. In Acta neuropathologica communications, 10, 136. doi:10.1186/s40478-022-01439-z. https://pubmed.ncbi.nlm.nih.gov/36076283/