- Role of mast cells and basophils in atherosclerosis
LE BORGNE M (1, 2), GAUTIER G (2, 3), LAUNAY P (3), and NICOLETTI A (1, 2)
- INSERM U1148 Laboratory of vascular translational science, Paris, France
- Université Paris Diderot, Paris, France
- INSERM U1149, Centre de recherche sur l’inflammation, Paris, France
Introduction: Mast cells (MCs) and basophils are pluripotent effector cells of the innate immune system. Recent findings suggest that they play a role in atherosclerosis, an alteration of large- and medium-size arteries that can lead to the development of cardiovascular complications such as myocardial and cerebral infarction or abdominal aortic aneurysm (AAA) formation and rupture. Cells of the innate and adaptive immunity are centrally involved in atherogenesis. B cells that infiltrate the arterial wall sometimes organize into tertiary lymphoid organs (TLOs) in the adventitia of the artery close to the lesions. However, how these structures forms, and their functions in atherosclerosis, remain poorly understood.
Methods: We will use the newly-developed RMB mouse model to explore to role of MCs and basophils in the pathophysiology of atherosclerosis. RMB mice have been generated by knocking-in a Tomato-hDTR (human diphtheria toxin receptor) cassette under the control of the FcεR1β promoter, which is specifically activated in MCs and basophils. By using single-, or repeated-DT injections, we can generate MC-only, or MCs+basophils-depleted mice, respectively. By crossing RMB mice to ApoE-deficient mice, which display extensive atherosclerotic lesions and adventitial TLO all along the aorta, we will test the effect DT injection(s) in RMBxApoE-/- mice on the incidence and size of atherosclerotic lesions, and on TLO development. In order to study the effect of MCs and basophils on AAA development, AAAs will be induced in ApoE-/-xRMB mice by angiotensin II-infusion. Finally, in order to understand how the lesion microenvironment affect MCs, and how MCs might in turn affect TLO formation, we will study the effect of conditioned medium from adventitia of ApoE-/- mice or AAA and normal patients on MC activation, degranulation, and cytokine and chemokine production.
Results: We have observed in preliminary experiments that MCs, but also basophils, are enriched in the vascular wall of AAAs from human patients. We have started to cross RMB mice to ApoE-/- mice.
Conclusions: We expect that our work will help to conclusively uncover the function of MCs, and basophils, in atherosclerosis progression, TLO formation and atherosclerotic complications such as AAAs. It might lead to the development of new therapeutic strategies targeting MCs and basophils in order to slow down atherosclerosis progression.