title: Lymphocytes influence intracranial aneurysm formation and rupture: role of extracellular matrix remodeling and phenotypic modulation of vascular smooth muscle cells.
abstract: Intracranial aneurysms (IA) are increasingly recognized as a disease driven by chronic inflammation. Recent research has identified key mediators and processes underlying IA pathogenesis, but mechanistic understanding remains incomplete. Lymphocytic infiltrates have been demonstrated in patient IA tissue specimens and have also been shown to play an important role in abdominal aortic aneurysms (AAA) and related diseases such as atherosclerosis. However, no study has systematically examined the contribution of lymphocytes in a model of IA.
  
  
  
  Lymphocyte-deficient (Rag1) and wild-type (WT; C57BL/6 strain) mice were subjected to a robust IA induction protocol. Rates of IA formation and rupture were measured, and cerebral artery tissue was collected and utilized for histology and gene expression analysis.
  
  
  
  At 2 weeks, the Rag1 group had significantly fewer IA formations and ruptures than the WT group. Histological analysis of unruptured IA tissue showed robust B and T lymphocyte infiltration in the WT group, while there were no differences in macrophage infiltration, IA diameter, and wall thickness. Significant differences in interleukin-6 (IL-6), matrix metalloproteinases 2 (MMP2) and 9 (MMP9), and smooth muscle myosin heavy chain (MHC) were observed between the groups.
  
  
  
  Lymphocytes are key contributors to IA pathogenesis and provide a novel target for the prevention of IA progression and rupture in patients.
authors.affiliation: Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Sawyer
authors.affiliation: Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Pace
authors.affiliation: Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA.
authors.forename: Crissey L
authors.initials: CL
authors.lastname: Pascale
authors.affiliation: Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Kutchin
authors.affiliation: Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA.
authors.forename: Brannan E
authors.initials: BE
authors.lastname: O'Neill
authors.affiliation: Department of Neurosurgery, University of Miami, Miami, FL, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Starke
authors.affiliation: Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA. adumont2@tulane.edu.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Dumont
mesh_terms: D017542:Aneurysm, Ruptured / Q000473:pathology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D002532:Intracranial Aneurysm / Q000235:genetics / Q000473:pathology*; D008214:Lymphocytes / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D024745:Smooth Muscle Myosins / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018398:Homeodomain Proteins; D015850:Interleukin-6; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D024745:Smooth Muscle Myosins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C064658:RAG-1 protein
keywords: Cerebral aneurysm; Inflammation; Interleukin-6; Leukocyte; Matrix metalloproteinase 2; Matrix metalloproteinase 9; Myosin heavy chain; Rag1 mice; Subarachnoid hemorrhage