Inhibition of LAR attenuates neuroinflammation through RhoA/IRS-1/Akt signaling pathway after intracerebral hemorrhage in mice

by Selleckchem | Jul 24 2023

Leukocyte common antigen-related phosphatase (LAR) is widely expressed in the central nervous system and is known to regulate a variety of processes including cell growth, differentiation, and inflammation. However, little is currently known about LAR signaling mediated neuroinflammation after intracerebral hemorrhage (ICH). The objective of this study was to investigate the role of LAR in ICH using autologous blood injection-induced ICH mouse model. Expression of endogenous proteins, brain edema and neurological function after ICH were evaluated. Extracellular LAR peptide (ELP), an inhibitor of LAR, was administered to ICH mice and outcomes were evaluated. LAR activating-CRISPR or IRS inhibitor NT-157 was administered to elucidate the mechanism. The results showed that expressions of LAR, its endogenous agonist chondroitin sulfate proteoglycans (CSPGs) including neurocan and brevican, and downstream factor RhoA increased after ICH. Administration of ELP reduced brain edema, improved neurological function, and decreased microglia activation after ICH. ELP decreased RhoA and phosphorylated serine-IRS1, increased phosphorylated tyrosine-IRS1 and p-Akt, and attenuated neuroinflammation after ICH, which was reversed by LAR activating-CRISPR or NT-157. In conclusion, this study demonstrated that LAR contributed to neuroinflammation after ICH via RhoA/IRS-1 pathway, and ELP may be a potential therapeutic strategy to attenuate LAR mediated neuroinflammation after ICH.

Comments:

The study you described investigated the role of leukocyte common antigen-related phosphatase (LAR) in neuroinflammation following intracerebral hemorrhage (ICH) using a mouse model. LAR is a protein that is widely expressed in the central nervous system and is involved in regulating various processes such as cell growth, differentiation, and inflammation.

To examine the role of LAR in ICH, the researchers induced ICH in mice by injecting autologous blood into the brain. They evaluated the expression of LAR and its associated proteins, the development of brain edema, and neurological function after ICH. In addition, they administered an extracellular LAR peptide (ELP), which is an inhibitor of LAR, to the ICH mice and assessed the outcomes.

The results of the study showed that the expression of LAR, as well as its endogenous agonists called chondroitin sulfate proteoglycans (CSPGs), including neurocan and brevican, increased after ICH. The downstream factor RhoA, which is involved in cellular processes, was also upregulated. However, when the researchers administered ELP, they observed a reduction in brain edema, improved neurological function, and decreased activation of microglia (a type of immune cell in the brain) after ICH.

Further analysis revealed that ELP treatment decreased the levels of RhoA and phosphorylated serine-IRS1 (insulin receptor substrate 1), while increasing phosphorylated tyrosine-IRS1 and p-Akt. These changes were associated with a decrease in neuroinflammation following ICH. Importantly, the effects of ELP were reversed when LAR activating-CRISPR (a gene-editing tool) or an IRS inhibitor called NT-157 were administered, suggesting that LAR's contribution to neuroinflammation after ICH occurs through the RhoA/IRS-1 pathway.

In conclusion, this study demonstrated that LAR plays a role in neuroinflammation following ICH through the RhoA/IRS-1 pathway. The administration of ELP, an inhibitor of LAR, showed potential as a therapeutic strategy to attenuate LAR-mediated neuroinflammation after ICH. These findings provide insights into the molecular mechanisms underlying neuroinflammation in ICH and suggest that targeting LAR signaling could be a promising approach for therapeutic intervention.