Lpar5-KO Mouse

Lpar5, also known as lysophosphatidic acid receptor 5, is a G protein-coupled receptor. It mediates the biological actions of lysophosphatidic acid (LPA), a bioactive lipid mediator, and is involved in various cellular functions such as cell proliferation, migration, and survival. Lpar5 has been associated with multiple signaling pathways like the ERK/Snail, PI3K/Akt, and RHO-ROCK-SRF axes [2,3,6,7]. It plays a crucial role in maintaining normal intestinal homeostasis and is involved in modulating pathological conditions including pain, itch, inflammatory diseases, and cancer [2].

In the context of stroke, overexpression of PARP14 suppresses Lpar5 gene transcription, which in turn inhibits microglial activation and promotes post-stroke functional recovery. Genetic knockdown of PARP14 leads to increased Lpar5 expression, aggravated functional impairment, and increased infarct volume in photothrombotic stroke mice, indicating that Lpar5 activation may have a negative impact on post-stroke recovery [1]. In cancer, LPAR5 has diverse roles. In non-small-cell lung carcinoma, it stimulates malignant progression by upregulating MLLT11. Knockdown of LPAR5 attenuates in vitro proliferative and migratory abilities of cancer cells and slows down in vivo tumor growth [5]. In thyroid carcinoma, LPAR5 promotes cell proliferation and migration by activating class IA PI3K catalytic subunit p110β, and treatment with a LPAR5-specific antagonist inhibits cell proliferation and migration both in vitro and in vivo [6]. In osteosarcoma, the infiltration of LPAR5+ macrophages in the tumor microenvironment predicts better outcomes, suggesting a potential protective role [4]. In non-small cell lung cancer with KRAS and TP53 mutations, autotaxin suppresses cytotoxic T cells via LPAR5, promoting anti-PD-1 resistance, and pharmacological inhibition of LPAR5 can restore the antitumor immune response [8].

In conclusion, Lpar5 is a key receptor involved in multiple biological functions and disease processes. Studies using gene-based models, such as genetic knockdown in mouse models for stroke and pharmacological inhibition of LPAR5 in cancer models, have revealed its role in post-stroke recovery and cancer progression. These findings suggest that Lpar5 could be a potential therapeutic target for stroke and various cancers.

References:

1. Tang, Ying, Liu, Jinchang, Wang, Yu, Xu, Yungen, Yao, Honghong. 2020. PARP14 inhibits microglial activation via LPAR5 to promote post-stroke functional recovery. In Autophagy, 17, 2905-2922. doi:10.1080/15548627.2020.1847799. https://pubmed.ncbi.nlm.nih.gov/33317392/

2. Dacheux, Mélanie A, Norman, Derek D, Tigyi, Gábor J, Lee, Sue Chin. 2023. Emerging roles of lysophosphatidic acid receptor subtype 5 (LPAR5) in inflammatory diseases and cancer. In Pharmacology & therapeutics, 245, 108414. doi:10.1016/j.pharmthera.2023.108414. https://pubmed.ncbi.nlm.nih.gov/37061203/

3. Sun, Xiao-Ya, Li, Hao-Zheng, Xie, Da-Fei, Bai, Chen-Jun, Zhou, Ping-Kun. 2022. LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway. In Journal of translational medicine, 20, 456. doi:10.1186/s12967-022-03673-4. https://pubmed.ncbi.nlm.nih.gov/36199069/

4. He, Yi, Zhou, Haiting, Huang, Xiaojian, Chen, Sheng, You, Hongbo. 2022. Infiltration of LPAR5+ macrophages in osteosarcoma tumor microenvironment predicts better outcomes. In Frontiers in immunology, 13, 909932. doi:10.3389/fimmu.2022.909932. https://pubmed.ncbi.nlm.nih.gov/36591220/

5. Zhang, H-P, Chen, Q-K, Xu, J-F. . LPAR5 stimulates the malignant progression of non-small-cell lung carcinoma by upregulating MLLT11. In European review for medical and pharmacological sciences, 24, 8902-8910. doi:10.26355/eurrev_202009_22831. https://pubmed.ncbi.nlm.nih.gov/32964980/

6. Zhao, Wei-Jun, Zhu, Liu-Lian, Yang, Wei-Qiang, Liang, Yong, Chen, Guang. 2021. LPAR5 promotes thyroid carcinoma cell proliferation and migration by activating class IA PI3K catalytic subunit p110β. In Cancer science, 112, 1624-1632. doi:10.1111/cas.14837. https://pubmed.ncbi.nlm.nih.gov/33540491/

7. Sumitomo, Akiko, Siriwach, Ratklao, Thumkeo, Dean, Aoki, Junken, Narumiya, Shuh. 2018. LPA Induces Keratinocyte Differentiation and Promotes Skin Barrier Function through the LPAR1/LPAR5-RHO-ROCK-SRF Axis. In The Journal of investigative dermatology, 139, 1010-1022. doi:10.1016/j.jid.2018.10.034. https://pubmed.ncbi.nlm.nih.gov/30447238/

8. Konen, Jessica M, Rodriguez, B Leticia, Wu, Haoyi, Zhang, Jianjun, Gibbons, Don L. 2023. Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti-PD-1 resistance in non-small cell lung cancer. In The Journal of clinical investigation, 133, . doi:10.1172/JCI163128. https://pubmed.ncbi.nlm.nih.gov/37655662/