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Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment
Almudena Ortega-Gomez1, Melanie Salvermoser1, Jan Rossaint1
1From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
Insights
Cathepsin G (CatG) is crucial for arterial leukocyte adhesion and atherosclerosis development. Inhibiting CatG specifically blocks arterial inflammation, offering a potential new treatment strategy for arterial diseases.
Area of Science:
- Cardiovascular Biology
- Immunology
- Vascular Inflammation
Background:
- Therapeutic strategies targeting arterial leukocyte recruitment in atherosclerosis have yielded disappointing clinical results.
- A lack of understanding regarding arterial-specific leukocyte recruitment patterns contributes to these failures.
- This study identifies cathepsin G (CatG) as a key mediator of myeloid cell recruitment within arteries.
Purpose of the Study:
- To investigate the role of cathepsin G (CatG) in arterial myeloid cell recruitment.
- To elucidate the mechanisms underlying arterial-specific leukocyte adhesion.
- To evaluate the therapeutic potential of targeting CatG in atherosclerosis.
Main Methods:
- Intravital microscopy was employed in Apoe-/- and CatG-deficient mice to observe myeloid cell behavior in arteries and veins.
- Atherosclerosis development was assessed in aortic root sections, and lung inflammation was evaluated after lipopolysaccharide inhalation.
- Endothelial deposition of CatG and CCL5 was quantified using advanced microscopy techniques.
Main Results:
- Cathepsin G (CatG) plays a critical role in arterial leukocyte adhesion, but not in venular adhesion.
- CatG deficiency significantly attenuated atherosclerosis development and atherogenesis in mice.
- CatG immobilized on arterial endothelium activates leukocytes, promoting firm adhesion via integrin clustering under high-shear conditions.
- Therapeutic neutralization of CatG specifically inhibited arterial leukocyte adhesion without affecting microcirculation adhesion.
Conclusions:
- Findings demonstrate an arterial-specific recruitment pattern driven by CatG-mediated adhesion strengthening.
- Inhibition of this CatG-dependent process presents a novel therapeutic strategy for arterial inflammation.
- Targeting CatG offers potential for treating arterial diseases with potentially limited side effects.
Background:
Therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis has been disappointing in clinical studies. Reasons for such failures include the lack of knowledge of arterial-specific recruitment patterns. Here we establish the importance of the cathepsin G (CatG) in the context of arterial myeloid cell recruitment.
Methods:
Intravital microscopy of the carotid artery, the jugular vein, and cremasteric arterioles and venules in Apoe-/-and CatG-deficient mice (Apoe-/-Ctsg-/-) was used to study site-specific myeloid cell behavior after high-fat diet feeding or tumor necrosis factor stimulation. Atherosclerosis development was assessed in aortic root sections after 4 weeks of high-fat diet, whereas lung inflammation was assessed after inhalation of lipopolysaccharide. Endothelial deposition of CatG and CCL5 was quantified in whole-mount preparations using 2-photon and confocal microscopy.
Results:
Our observations elucidated a crucial role for CatG during arterial leukocyte adhesion, an effect not found during venular adhesion. Consequently, CatG deficiency attenuates atherosclerosis but not acute lung inflammation. Mechanistically, CatG is immobilized on arterial endothelium where it activates leukocytes to firmly adhere engaging integrin clustering, a process of crucial importance to achieve effective adherence under high-shear flow. Therapeutic neutralization of CatG specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of CatG-neutralizing antibodies permitted inhibition of atherogenesis in mice.
Conclusions:
Taken together, these findings present evidence of an arterial-specific recruitment pattern centered on CatG-instructed adhesion strengthening. The inhibition of this process could provide a novel strategy for treatment of arterial inflammation with limited side effects.
