Homer1 promotes the conversion of A1 astrocytes to A2 astrocytes and improves the recovery of transgenic mice after intracerebral hemorrhage

Abstract

Background Inflammation induced by intracerebral hemorrhage (ICH) is one of the main causes of the high mortality and poor prognosis of patients with ICH. A1 astrocytes are closely associated with neuroinflammation and neurotoxicity, whereas A2 astrocytes are neuroprotective. Homer scaffolding protein 1 (Homer1) plays a protective role in ischemic encephalopathy and neurodegenerative diseases. However, the role of Homer1 in ICH-induced inflammation and the effect of Homer1 on the phenotypic conversion of astrocytes remain unknown. Methods Femoral artery autologous blood from C57BL/6 mice was used to create an ICH model. We use the A1 phenotype marker C3 and A2 phenotype marker S100A10 to detect astrocyte conversion after ICH. Homer1 overexpression/knock-down mice were constructed by adeno-associated virus (AAV) infection to explore the role of Homer1 and its mechanism of action after ICH. Finally, Homer1 protein and selumetinib were injected into in situ hemorrhage sites in the brains of Homer1flox/flox/Nestin-Cre+/− mice to study the efficacy of Homer1 in the treatment of ICH by using a mouse cytokine array to explore the potential mechanism. Results The expression of Homer1 peaked on the third day after ICH and colocalized with astrocytes. Homer1 promotes A1 phenotypic conversion in astrocytes in vivo and in vitro. Overexpression of Homer1 inhibits the activation of MAPK signaling, whereas Homer1 knock-down increases the expression of pathway-related proteins. The Homer1 protein and selumetinib, a non-ATP competitive MEK1/2 inhibitor, improved the outcome in ICH in Homer1flox/flox/Nestin-Cre+/− mice. The efficacy of Homer1 in the treatment of ICH is associated with reduced expression of the inflammatory factor TNFSF10 and increased expression of the anti-inflammatory factors activin A, persephin, and TWEAK. Conclusions Homer1 plays an important role in inhibiting inflammation after ICH by suppressing the A1 phenotype conversion in astrocytes. In situ injection of Homer1 protein may be a novel and effective method for the treatment of inflammation after ICH.

Glial cells: an important switch for the vascular function of the central nervous system

“…BBB dysfunction in intracerebral hemorrhage involves glial in the brain. Astrocytic conversion plays a role in the post-inflammatory response of intracerebral hemorrhage ( Fei et al, 2022 ). Astrocyte-related post-inflammation further aggravates BBB leakage and enhances permeability.…”

The role of the astrocyte in subarachnoid hemorrhage and its therapeutic implications

“…H2-D1, C3 and serping1 are markers for the A1 subtype, and pentraxin 3 (PTX3), sphingosine-1-phosphate receptor 3 (S1PR3) and S100 calcium-binding protein A10 (S100A10) are markers for the A2 subtype of reactive astrocytes ( 23 ). Recent research has shown that C3 and serping1 immunoreactivity are the common markers that represent the A1 phenotype, while S100A10 and PTX3 are the common markers of A2 astrocytes ( 24 – 28 ). Animal research showed that astrocytes were transformed into A1 astrocytes, and A1 astrocytes caused cell death by releasing proinflammatory factors after SAH ( 5 ).…”

Progress in Research on TLR4-Mediated Inflammatory Response Mechanisms in Brain Injury after Subarachnoid Hemorrhage

“…These protrusions, which stretch and fill between the cell bodies of nerve cells and their protrusions, play the role of supporting and separating nerve cells and participate in the blood–brain barrier formation [ 132 , 158 ]. Astrocytes can differentiate into diverse phenotypes under different stimuli, namely, pro-inflammatory type (type A1) and anti-inflammatory one (type A2) [ 159 , 160 , 161 ]. SAH contributes to the transformation of astrocytes into type A1.…”