Perivascular macrophages control the severity of experimental autoimmune encephalomyelitis

About This Grant

Summary Central Nervous system (CNS) perivascular macrophages are part of a group of macrophages names border- associated macrophages (BAM). Most BAM are generated during embryogenesis and maintained by self- division. We developed a genetic system in which the main type of BAM (CD206H) is ablated in the brain. When experimental autoimmune encephalomyelitis (EAE) is induced in these BAM-ablated mice, the disease is much more severe, indicating that healthy BAM are generally protective from neuroinflammatory diseases such as EAE. Given that in the CNS perivascular BAM are located in the perivascular space formed between the endothelium and the astrocyte feet that delimit the blood-brain barrier (BBB), we hypothesize that this unique location endows BAM with the capacity to reinforce the BBB thereby limiting the flow of inflammatory cells into the CNS. In contrast to BAM, monocyte-derived macrophages are not resident of the CNS but swiftly enter into the CNS in diseases such as EAE and multiple sclerosis (MS), together with a large number of other inflammatory myeloid and lymphoid cells. In contrast to what we hypothesize is the function of BAM, monocyte-derived macrophages are known to be part of the pathogenesis of EAE and MS, being considered the main executioners of demyelination through phagocytosis of pieces of myelin. In this R21 application, we propose to test the hypothesis that healthy perivascular BAM contribute to the barrier function of the BBB. We will also determine whether BAM, a subgroup of which express MHC class II, can affect the activation profile of T cells. We propose two specific aims. In Aim 1, we will induce EAE in mice that lack BAM and mice with normal BAM and will monitor daily the inflow of inflammatory cells (myeloid and lymphoid) into the spinal cord of mice. We will inject monocytes labeled at the Ccr2 locus to follow the fate of monocyte-derived CCR2+ macrophages inside the inflamed CNS, and monitor the permeability of the BBB under unstimulated conditions or EAE in mice. In Aim 2, we will focus on the differences that BAM presence or absence would make on the T cell activation state and cytokines produced, We will also bypass the priming in lymph nodes by using the adoptive transfer model of activated T cells and monitor the fate of these T cells in mice with normal BAM versus ablated BAM. Finally, in collaboration with Dr Gabriel Victora, we will use a novel mouse strain, named uLipstic, to label T cells and identify what are the CNS cells that first interact with myelin-reactive T cells. At the end of the proposed studies, we will deliver a clear picture of whether perivascular CNS-resident BAM are an important player in EAE, thus suggesting that reinforcing the BAM compartment could have a beneficial impact in neuroinflammatory diseases.