Pericytes regulate vascular immune homeostasis in the CNS

Abstract

21Brain endothelium possesses several organ-specific features collectively known as the blood-22 brain barrier (BBB). In addition, trafficking of immune cells in the healthy central nervous 23 system (CNS) is tightly regulated by CNS vasculature. In CNS autoimmune diseases such as 24 multiple sclerosis (MS), these homeostatic mechanisms are overcome by autoreactive 25 2 lymphocyte entry into the CNS causing inflammatory demyelinating immunopathology. 26Previous studies have shown that pericytes regulate the development of organ-specific 27 characteristics of brain vasculature such as the BBB and astrocytic end-feet. Whether pericytes 28 are involved in the control of leukocyte trafficking remains elusive. Using adult, pericyte-29 deficient mice (Pdgfb ret/ret ), we show here that brain vasculature devoid of pericytes shows 30 increased expression of VCAM-1 and ICAM-1, which is accompanied by increased leukocyte 31 infiltration of dendritic cells, monocytes and T cells into the brain, but not spinal cord 32 parenchyma. Regional differences enabling leukocyte trafficking into the brain as opposed to 33 the spinal cord inversely correlate with the pericyte coverage of blood vessels. Upon induction 34 of experimental autoimmune encephalitomyelitis (EAE), pericyte-deficient mice succumb to 35 severe neurological impairment. Treatment with first line MS therapy -fingolimod significantly 36 reverses EAE, indicating that the observed phenotype is due to the massive influx of immune 37 cells into the brain. Furthermore, pericyte-deficiency in mice that express myelin 38 oligodendrocyte glycoprotein peptide (MOG35-55) specific T cell receptor (Pdgfb ret/ret ; 2D2 Tg ) 39 leads to the development of spontaneous neurological symptoms paralleled by massive influx 40 of leukocytes into the brain, suggesting altered brain vascular immune quiescence as a prime 41 cause of exaggerated neuroinflammation. Thus, we show that pericytes indirectly restrict 42 immune cell transmigration into the CNS under homeostatic conditions and during 43 autoimmune-driven neuroinflammation by inducing immune quiescence of brain endothelial 44 cells. 45 46 leukocytes into brain parenchyma, thus contributing to immune privilege of the CNS. BBB 51 function is induced by neural tissue and established by all cell types constituting the 52 neurovascular unit (NVU). Pericytes and mural cells residing on the abluminal side of 53 capillaries and post-capillary venules, regulate several features of the BBB 1, 2 . Studies on Pdgfb 54and Pdgfrb mouse mutants, which exhibit variable pericyte loss, have demonstrated that 55 pericytes negatively regulate endothelial transcytosis which, if not suppressed, leads to 56 increased BBB permeability to plasma proteins 1, 2 . In addition, pericyte-deficient vessels show 57 abnormal astrocyte end-feet polarization 1 . Thus, pericytes regulate several characteristics of 58 brain vasculature during development and in the adult organism 1, 2 . Whether the non-59 permissive properties of brain vasculature to leukocyte traffic...

Cardiovascular disease causes proinflammatory microvascular changes in the human right atrium

“…Interestingly, one of the central players in the disease progression were pericytes that presented strong disease-associated signatures in all three disease groups suggesting that this cell-type may constitute an under-appreciated driver of heart disease. Previous studies have documented pericytes as critical for the maintenance of the blood brain barrier and homeostasis in the central nervous system 25,26 , as well as for the production of paracrine factors targeting capillary endothelial cells to promote an anti-thrombotic endothelial phenotype 27 .…”

Cytokines in CAR T Cell–Associated Neurotoxicity

“…It is becoming increasingly clear that pericyte adhesion to the endothelium is required for regulating leukocyte diapedesis during systemic inflammation (178). For example, pericyte deficient mice have increased expression of the leukocyte adhesion molecules VCAM-1 and ICAM-1 on cerebral endothelial cells, leading to increased perivascular immune cell infiltration (179). After systemic LPS injection, pericytes detach from the basal lamina, thereby increasing BBB permeability to infiltrating cells (166).…”

Transmigration across a Steady-State Blood–Brain Barrier Induces Activation of Circulating Dendritic Cells Partly Mediated by Actin Cytoskeletal Reorganization

“…First, pericytes were not included in the in vitro model of the BBB used here. Nonetheless, previous reports have established that pericytes play a critical role in the integration of endothelial and astrocyte function at the neurovascular unit, and in the regulation of the BBB in vitro [ 9 , 11 , 24 ]. Hence, including pericytes in an in vitro model of the BBB could provide additional phenotypic advantages in mimicking the in vivo BBB.…”

“…The crosstalk and molecular signaling between these different cell types are collectively known as the neurovascular unit, which allows the BBB to properly perform its fundamental physiological functions. Other than that, pericytes play a critical role during angiogenesis and regulating immune cell infiltration [ 9 ]. In addition, these cells have been shown to be important for regulating the formation of the BBB during development, as well as maintaining its function in adulthood and aging [ 10 ].…”