Group 2 Innate Lymphoid Cells Protect Mice from Abdominal Aortic Aneurysm Formation via IL5 and Eosinophils

Abstract

Development of abdominal aortic aneurysms (AAA) enhances lesion group‐2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/flIl7rCre/+ mice or induced ILC2 depletion in Icosfl‐DTR‐fl/+Cd4Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild‐type (WT) mice, but not ILC2 from Il5−/− mice induces EOS differentiation in bone‐marrow cells from Rorafl/flIl7rCre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5−/− and Il13−/− mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5−/− mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6Chi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5−/− ILC2 slows AAA growth in Rorafl/flIl7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism.

Colchicine Blocks Abdominal Aortic Aneurysm Development by Maintaining Vascular Smooth Muscle Cell Homeostasis

“…All mice were housed under a 12-hour light/dark cycle in a pathogen-free animal facility with free access to food and water. Subcutaneous angiotensin-II (Ang-II) infusion- and peri-aortic CaPO 4 injury-induced AAA was performed as described previously 21 , 22 . Briefly, mice were anaesthetized with ketamine (100 mg/kg) and pentobarbital sodium (50 mg/kg).…”

“…Immunohistochemical and immunofluorescent staining were performed as described previously [21][22][23]. Briefly, serial cryostat sections (6 μm) from mice or paraffin sections (6 μm) from human AAA lesion were prepared and processed for immuno-staining to detect α-smooth muscle actin (α-SMA, 1:100, A17910, ABclonal), Mac2 (1:100, CL8942AP, Cedarlane, Burlington, Canada) and CD31 (1:250, ab7388, Abcam, Cambridge, MA).…”

Regulatory T cells and cardiovascular diseases

“…[22] The role of type 2 immune responses is ambiguous in CVDs, but type 2 innate lymphoid cells (ILC2s), which have a similar secretion profile to Th2, play a protective role in AS, MI, and AAA via IL-5/IL-13. [23][24][25] In addition, Tregs directly interact with ILC2s, secrete IL-10 and TGF-b to expand ILC2 population and promote IL-13 secretion. [26] Indoleamine 2,3-dioxygenase controls the kynurenine pathway, regulates T-cell-mediated inflammatory response, and induces tolerance.…”

“…In addition to their ability to secrete IL-10 to promote the polarization of macrophages to the anti-inflammatory phenotype M2, Tregs can inhibit CD80/CD86 by expressing CTLA-4, thereby downregulating the expression of proinflammatory factors and matrix metalloproteinases (MMPs) [22] . The role of type 2 immune responses is ambiguous in CVDs, but type 2 innate lymphoid cells (ILC2s), which have a similar secretion profile to Th2, play a protective role in AS, MI, and AAA via IL-5/IL-13 [23–25] . In addition, Tregs directly interact with ILC2s, secrete IL-10 and TGF-β to expand ILC2 population and promote IL-13 secretion [26] .…”

Group 2 innate lymphoid cells suppress neuroinflammation and brain injury following intracerebral hemorrhage

“…15 As a critical innate source of type 2 effector cytokines, ILC2 produce cytokines such as IL-13 to control the initiation and resolution of tissue inflammation. [16][17][18] Given the prompt nature of the ILC2 in response to tissue injury without need for antigen presentation and the rapid evolution of PHE, we postulated that ILC2 would play a major role in control of neuroinflammation following ICH.…”