Toll-Like Receptor 2 Attenuates the Formation and Progression of Angiotensin II-Induced Abdominal Aortic Aneurysm in ApoE-/- Mice

J Vasc Res. 2024;61(6):304-317. doi: 10.1159/000541651. Epub 2024 Oct 28.

Abstract

Introduction: We demonstrated Toll-like receptor (TLR) 4 in the pathogenesis of angiotensin II (AngII)-mediated abdominal aortic aneurysm (AAA) formation. Here, we study TLR2 in the AAA formation.

Methods: Male ApoE-/- and ApoE-/-TLR2-/- mice were treated with AngII. Mice were injected with the TLR2 agonist Pam3CSK4. The incidence and severity of AAA were determined. MCP-1, MCP-5, RANTES, CXCL10, CCR5, and CXCR3 were analyzed. M1 and M2 macrophages in the aorta were detected by flow cytometry.

Results: These studies demonstrated an increase in AAA formation in TLR2-/- mice and a decrease by Pam3CSK4. Pam3CSK4 decreased the ratio of M1/M2 and the levels of RANTES, CXCL10, CCR5, and CXCR3. Furthermore, Pam3CSK4 treatment 1 week following AngII retarded the progression of AAA.

Conclusion: These data demonstrated a protective effect of TLR2 signaling on AAA in association with a decrease in the ratio of M1 to M2 macrophages and the expression of chemokines and their receptors. Furthermore, the treatment of Pam3CSK4 after AngII demonstrated a marked retardation of lesion progression. Given the fact that most AAA patients are detected late in the disease process, these findings suggest that TLR2 stimulation may play a therapeutic role in retarding disease progression.

Keywords: Abdominal aortic aneurysm; CCR5/CXCR3 inhibitor TAK-779; M1/M2 macrophage ratio; Pam3CSK4; Toll-like receptor 2.

MeSH terms

  • Angiotensin II*
  • Animals
  • Aorta, Abdominal / drug effects
  • Aorta, Abdominal / metabolism
  • Aorta, Abdominal / pathology
  • Aortic Aneurysm, Abdominal* / chemically induced
  • Aortic Aneurysm, Abdominal* / genetics
  • Aortic Aneurysm, Abdominal* / metabolism
  • Aortic Aneurysm, Abdominal* / pathology
  • Aortic Aneurysm, Abdominal* / prevention & control
  • Apolipoproteins E
  • Disease Models, Animal*
  • Disease Progression*
  • Lipopeptides* / pharmacology
  • Macrophages* / drug effects
  • Macrophages* / metabolism
  • Macrophages* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Mice, Knockout, ApoE*
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / metabolism
  • Signal Transduction*
  • Time Factors
  • Toll-Like Receptor 2* / deficiency
  • Toll-Like Receptor 2* / genetics
  • Toll-Like Receptor 2* / metabolism

Substances

  • Toll-Like Receptor 2
  • Angiotensin II
  • Tlr2 protein, mouse
  • Pam(3)CSK(4) peptide
  • Lipopeptides
  • Receptors, CXCR3
  • Cxcr3 protein, mouse
  • Receptors, CCR5
  • CCR5 protein, mouse
  • Apoe protein, mouse
  • Apolipoproteins E