RT Journal Article
SR Electronic
T1 CLMP Promotes Leukocyte Migration Across Brain Barriers in Multiple Sclerosis
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e200022
DO 10.1212/NXI.0000000000200022
VO 9
IS 6
A1 Antoine Philippe Fournier
A1 Stephanie Zandee
A1 Marc Charabati
A1 Evelyn Peelen
A1 Olivier Tastet
A1 Jorge Ivan Alvarez
A1 Hania Kebir
A1 Lyne Bourbonnière
A1 Sandra Larouche
A1 Boaz Lahav
A1 Wendy Klement
A1 Fiona Tea
A1 Alain Bouthillier
A1 Robert Moumdjian
A1 Romain Cayrol
A1 Pierre Duquette
A1 Marc Girard
A1 Catherine Larochelle
A1 Nathalie Arbour
A1 Alexandre Prat
YR 2022
UL http://nn.neurology.org/content/9/6/e200022.abstract
AB Background and Objectives In multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor–like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS.Methods Expression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP.Results Using bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNFα-activated and IFNγ-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP+ B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP+ immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS.Discussion Collectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions.ALCAM=activated leukocyte cell adhesion molecule; BBB=blood-brain barrier; BMB=blood-CSF meningeal barrier; CAM=cellular adhesion molecule; CAR=coxsackie and adenovirus receptor; CLMP=CAR-like membrane protein; EC=endothelial cell; HBEC=human brain EC; HMEC=human meningeal EC; ICAM-1=intercellular adhesion molecule 1; IFNγ=interferon gamma; IgSF=immunoglobulin superfamily; JAM=junctional adhesion molecule; MS=multiple sclerosis; ORO=oil red O; PBMC=peripheral blood mononuclear cell; TBST=tris-buffered saline–0.1% Tween; TNFα=tumor necrosis factor alpha; VCAM-1=vascular cell adhesion molecule 1