PMID- 37223093
OWN - NLM
STAT- MEDLINE
DCOM- 20230526
LR  - 20230612
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 14
DP  - 2023
TI  - Axl promotes intracranial aneurysm rupture by regulating macrophage polarization 
      toward M1 via STAT1/HIF-1alpha.
PG  - 1158758
LID - 10.3389/fimmu.2023.1158758 [doi]
LID - 1158758
AB  - BACKGROUND: Macrophage infiltration and polarization are crucial for the 
      pathogenesis of intracranial aneurysm (IA) rupture. Axl, a receptor tyrosine 
      kinase, is involved in inflammation and efferocytosis in multiple organs. 
      Upregulated soluble Axl in cerebrospinal fluid (CSF) and plasma is correlated 
      with intracranial aneurysm rupture. This study aimed to investigate the role of 
      Axl in IA rupture and macrophage polarization. METHODS: Male C57BL/6J mice were 
      used to induce IA. The level of Axl from control vessels and unruptured and 
      ruptured IA samples was detected. In addition, the relationship between Axl and 
      macrophages was confirmed. The pathway of Axl-mediated macrophage polarization 
      was explored after IA induction in vivo and in bone marrow-derived macrophages 
      (BMDMs) stimulated by LPS/IFN-gamma in vitro. The animals were randomized into three 
      groups and treated intraperitoneally with the vehicle, selective AXL antagonist 
      R428, and recombinant mouse growth arrest-specific 6 (rmGas6) for 21 consecutive 
      days. Then, we evaluated the influence of Axl on IA rupture by administrating 
      R428 to inhibit or rmGas6 to activate the Axl receptor in vivo. RESULTS: Compared 
      with that in normal vessels, Axl expression was significantly upregulated in 
      unruptured IA samples. The ruptured IA tissue exhibited significantly higher 
      expression of Axl than the unruptured IA tissue. Axl and F4/80 were coexpressed 
      in IA tissue and LPS/IFN-gamma-stimulated BMDMs. R428 treatment significantly reduced 
      the rate of M1-like macrophage infiltration and IA rupture. In contrast, rmGas6 
      treatment promoted M1 macrophage infiltration and IA rupture. Mechanistically, 
      R428 inhibited the phosphorylation of Axl and STAT1 and the expression of 
      hypoxia-inducible factor-1alpha (HIF-1alpha) and decreased the levels of IL-1beta, NOS2, and 
      MMP9 in LPS/IFN-gamma-stimulated BMDMs. rmGas6 promoted the phosphorylation of Axl 
      and STAT1 and the expression of HIF-1alpha. In addition, STAT1 knockdown abolished 
      Axl-mediated M1 macrophage polarization. CONCLUSION: The inhibition of Axl 
      reduced macrophage polarization toward the M1 phenotype via the STAT1/HIF-1alpha 
      signaling pathway and prevented IA rupture in mice. This finding suggests that 
      pharmacological inhibition of Axl might be used to prevent the progression and 
      rupture of IA.
CI  - Copyright (c) 2023 Han, Li, Zhang, Zhang, Zhao and Yang.
FAU - Han, Yongquan
AU  - Han Y
AD  - Department of Neurosurgery, the Affiliated Hospital of Guizhou Medical 
      University, Guiyang, China.
AD  - Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University School 
      of Medicine, Shanghai, China.
FAU - Li, Gaozhi
AU  - Li G
AD  - Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University School 
      of Medicine, Shanghai, China.
FAU - Zhang, Zeyu
AU  - Zhang Z
AD  - Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University School 
      of Medicine, Shanghai, China.
FAU - Zhang, Xiaohua
AU  - Zhang X
AD  - Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University School 
      of Medicine, Shanghai, China.
FAU - Zhao, Bing
AU  - Zhao B
AD  - Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University School 
      of Medicine, Shanghai, China.
FAU - Yang, Hua
AU  - Yang H
AD  - Department of Neurosurgery, the Affiliated Hospital of Guizhou Medical 
      University, Guiyang, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230508
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Stat1 protein, mouse)
RN  - 0 (STAT1 Transcription Factor)
SB  - IM
MH  - Male
MH  - Animals
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - *Intracranial Aneurysm
MH  - Lipopolysaccharides/pharmacology
MH  - *Aneurysm, Ruptured
MH  - Macrophages
MH  - STAT1 Transcription Factor
PMC - PMC10200875
OTO - NOTNLM
OT  - Axl
OT  - HIF-1alpha
OT  - STAT1
OT  - intracranial aneurysm
OT  - macrophage polarization
OT  - rupture
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/05/24 13:08
MHDA- 2023/05/26 06:42
PMCR- 2023/01/01
CRDT- 2023/05/24 11:41
PHST- 2023/02/04 00:00 [received]
PHST- 2023/04/27 00:00 [accepted]
PHST- 2023/05/26 06:42 [medline]
PHST- 2023/05/24 13:08 [pubmed]
PHST- 2023/05/24 11:41 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2023.1158758 [doi]
PST - epublish
SO  - Front Immunol. 2023 May 8;14:1158758. doi: 10.3389/fimmu.2023.1158758. 
      eCollection 2023.