Paired immunoglobulin-like receptor B (PirB) is an immune-inhibitory receptor, with its human ortholog being LILRB2. PirB is involved in multiple biological processes. In the immune system, it likely plays a role in regulating immune cell functions. In the nervous system, it has been associated with pathways affecting axonal regeneration, synaptic plasticity, and neural stem cell regulation [2,3,6].

In non-alcoholic steatohepatitis (NASH), PirB/LILRB2 binds with ANGPTL8 to regulate macrophage migration. Hepatocyte-specific ANGPTL8 knockout reduces macrophage infiltration, lipid accumulation, and fibrosis in NASH mice. PirB-/-bone marrow chimeras can abrogate ANGPTL8-induced macrophage migration to the liver, indicating PirB's role in NASH pathogenesis [1].

In the hippocampal neural stem cells of adult mice, PirB deficiency promotes neural stem cell proliferation and differentiation in vivo and in vitro, suggesting its inhibitory role in self-renewal and differentiation of neural stem cells [2].

In CNS injury, suppression of PirB activity can partially relieve the inhibition of neurite outgrowth in vitro and in vivo, highlighting its potential as a therapeutic target for enhancing axonal regeneration and synaptic plasticity [3].

In a mouse model of sleep deprivation, PirB negatively regulates the inflammatory activation of astrocytes via the STAT3 signaling pathway [4].

PirB-deficient mice lack hippocampal circuit asymmetries, suggesting that MHCI signals generating these asymmetries are transduced through PirB [5].

In diabetes-associated cognitive dysfunction, ANGPTL8 acts via PirB in neurons and microglia, leading to neuroinflammation and synaptic damage, and PirB-/-mice are resistant to ANGPTL8-induced effects [7].

In cerebral ischemia, PirB is upregulated, and soluble PirB ectodomain can improve recovery, indicating its potential as a theranostic target for ischemic stroke [8].

In conclusion, PirB plays diverse and significant roles in multiple biological processes and disease conditions. Gene knockout mouse models, such as PirB-/-mice, have been crucial in revealing PirB's functions in NASH, neural stem cell regulation, CNS injury, sleep-deprivation-related neuroinflammation, hippocampal circuit asymmetry, diabetes-associated cognitive dysfunction, and cerebral ischemia. These findings offer potential therapeutic targets for related diseases.

References:

1. Li, Dan-Pei, Huang, Li, Kan, Ran-Ran, Chen, Yong, Yu, Xue-Feng. 2023. LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis. In Nature communications, 14, 4436. doi:10.1038/s41467-023-40183-3. https://pubmed.ncbi.nlm.nih.gov/37481670/

2. Liu, Baiyang, Cheng, Wenjing, Cheng, Dating, Chen, Yongbin, Yang, Cuiping. 2021. PirB functions as an intrinsic suppressor in hippocampal neural stem cells. In Aging, 13, 16062-16071. doi:10.18632/aging.203134. https://pubmed.ncbi.nlm.nih.gov/34120891/

3. Gou, Zhaoyu, Mi, Yajing, Jiang, Fengliang, Yang, Jun, Gou, Xingchun. 2014. PirB is a novel potential therapeutic target for enhancing axonal regeneration and synaptic plasticity following CNS injury in mammals. In Journal of drug targeting, 22, 365-71. doi:10.3109/1061186X.2013.878939. https://pubmed.ncbi.nlm.nih.gov/24405091/

4. Li, Liya, Mou, Yan, Zhai, Qian, Wang, Qiang, Xiao, Zhaoyang. 2023. PirB negatively regulates the inflammatory activation of astrocytes in a mouse model of sleep deprivation. In Neuropharmacology, 235, 109571. doi:10.1016/j.neuropharm.2023.109571. https://pubmed.ncbi.nlm.nih.gov/37146940/

5. Ukai, Hikari, Kawahara, Aiko, Hirayama, Keiko, Takai, Toshiyuki, Ito, Isao. 2017. PirB regulates asymmetries in hippocampal circuitry. In PloS one, 12, e0179377. doi:10.1371/journal.pone.0179377. https://pubmed.ncbi.nlm.nih.gov/28594961/

6. Bi, Yong-Yan, Quan, Yong. 2017. PirB inhibits axonal outgrowth via the PI3K/Akt/mTOR signaling pathway. In Molecular medicine reports, 17, 1093-1098. doi:10.3892/mmr.2017.7930. https://pubmed.ncbi.nlm.nih.gov/29115495/

7. Meng, Xiaoyu, Li, Danpei, Kan, Ranran, Yang, Yan, Yu, Xuefeng. 2024. Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway. In Journal of neuroinflammation, 21, 192. doi:10.1186/s12974-024-03183-8. https://pubmed.ncbi.nlm.nih.gov/39095838/

8. Wang, Jie, Zhang, Ying, Xia, Jing, Zhang, Jianqiong, Teng, Gaojun. 2018. Neuronal PirB Upregulated in Cerebral Ischemia Acts as an Attractive Theranostic Target for Ischemic Stroke. In Journal of the American Heart Association, 7, . doi:10.1161/JAHA.117.007197. https://pubmed.ncbi.nlm.nih.gov/29378731/