Stromal Cell Niches in the Inflamed Central Nervous System Natalia B. Pikor, Jovana Cupovic, Lucas Onder, Jennifer L. Gommerman and Burkhard Ludewig This information is current as of September 23, 2021. J Immunol 2017; 198:1775-1781; ; doi: 10.4049/jimmunol.1601566 http://www.jimmunol.org/content/198/5/1775 Downloaded from References This article cites 91 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/198/5/1775.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Stromal Cell Niches in the Inflamed Central Nervous System Natalia B. Pikor,*,1 Jovana Cupovic,*,1 Lucas Onder,* Jennifer L. Gommerman,† and Burkhard Ludewig* Inflammation in the CNS must be tightly regulated to recruit and maintain T and B lymphocytes within defined respond efficiently to infection with neurotropic path- microenvironmental niches (3–5) and generate a conduit ogens. Access of immune cells to the CNS and their system that facilitates the delivery of Ag and small signaling positioning within the tissue are controlled by stromal molecules (6). Under inflammatory conditions, transcrip- cells that construct the barriers of the CNS. Although tional changes within these immune-stimulating stromal the role of the endothelium in regulating the passage of cells support the increased migration of lymphocytes into leukocytes and small molecules into the CNS has been the lymph node (LN) (7), the extraction and presentation of Downloaded from studied extensively, the contribution of fibroblastic Ag (8), and the repositioning of cognate T and B cells to stromal cells as portals of entry into the CNS was only increase the efficiency of immune cell activation and dif- recently uncovered. We review the critical immune- ferentiation (4). stimulating role of meningeal fibroblasts in promoting Notably, stromal cells at nonlymphoid sites may also be endowed with immune-stimulating functions under homeo- recruitment and retention of lymphocytes during CNS http://www.jimmunol.org/ static or inflammatory conditions. In the steady-state, dermal inflammation. Activated meningeal fibroblastic stromal and lung-resident stromal cells produce CCL19 and CCL21 to cells have the capacity to rapidly elaborate an immune- regulate lymphocyte recruitment to the organ (9, 10). These competent niche that sustains protective immune cells immunological functions may be enhanced upon inflamma- entering the CNS from the draining cervical lymph tory stimuli, as demonstrated by the upregulated expression node. Such stromal cell niches can ultimately foster of lymphoid chemokines and maturation of lymphoid-like the establishment of tertiary lymphoid tissues during fibroblasts in the lungs following viral infection (11). More- chronic neuroinflammatory conditions. The Journal over, chronic peripheral inflammation, as in the case of auto- of Immunology, 2017, 198: 1775–1781. immunity or tumors, may also result in persistent lymphocyte by guest on September 23, 2021 accumulation and maturation of immune-stimulating fibro- tromal cells build the infrastructure of an organ, en- blasts in organized ectopic aggregates commonly referred to suring its specific form, nutrient and oxygen supply, as tertiary lymphoid tissues (TLTs) (12). Certain aspects of S innervation, and drainage. Embedded into the frame- lymphoid-like stromal cell activation were observed in the CNS work of stromal cells are the cells of a tissue’s parenchyma, following acute pathogenic infection, as well as in the context which define the specific function of the organ. In secondary of CNS autoimmunity. In this article, we review the spatial lymphoid organs (SLOs), fibroblastic reticular cells (FRCs), distribution of stromal cells in the CNS, with emphasis on blood endothelial cells (BECs), and lymphatic endothelial meningeal fibroblastic stromal cells, and highlight their im- cells (LECs) represent stromal cell populations that ensure munological function and pathways of activation during acute structural compartmentalization and immunological function and chronic neuroinflammatory processes. of these tissues. Aside from their role in maintaining the unique architecture of SLOs, stromal cells play a critical role in pro- Stromal cells: gatekeepers to the CNS parenchyma moting immune responses. CD31+ podoplanin (PDPN)+ LECs CNS stromal cells comprise BECs and their surrounding 2 and CD31+ PDPN BECs regulate lymphocyte migration into pericytes and smooth muscle cells, meningeal fibroblasts, and out of SLOs (1, 2), whereas specialized populations of LECs, and epithelial cells of the choroid plexus. Importantly, 2 CD31 PDPN+ FRCs produce chemokines and cytokines that the anatomically defined position and interaction of these *Institute of Immunobiology, Kantonsspital St. Gallen, CH-9007 St. Gallen, Switzer- Address correspondence and reprint requests to Prof. Burkhard Ludewig, Institute of land; and †Department of Immunology, University of Toronto, Toronto, Ontario M5S Immunobiology, Kantonsspital St. Gallen, Rorschacherstrasse 95, CH-9007 St. Gallen, 1A8, Canada Switzerland. E-mail address: [email protected] 1N.B.P. and J.C. contributed equally to this work. Abbreviations used in this article: BBB, blood–brain barrier; BEC, blood endothelial cell; BM, basement membrane; EAE, experimental autoimmune encephalomyelitis; ECM, Received for publication September 7, 2016. Accepted for publication October 19, extracellular matrix; FDC, follicular dendritic cell; FRC, fibroblastic reticular cell; 2016. LCMV, lymphocytic choriomeningitis virus; LEC, lymphatic endothelial cell; LN, This work was supported by grants from the Swiss Multiple Sclerosis Society, Stiftung lymph node; LT, lymphotoxin; LTbR, LT-b receptor; MS, multiple sclerosis; PDGFR, OPOS Zugunsten von Wahrnehmungsbehinderten, and the Helmut Horten Founda- platelet-derived growth factor receptor; PDPN, podoplanin; SLO, secondary lymphoid tion and Swiss National Science Foundation Grant 146133 (all to B.L.). organ; TLT, tertiary lymphoid tissue; TRM, tissue-resident memory T; VSMC, vascular smooth muscle cell. The funders had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript. Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601566 1776 BRIEF REVIEWS: REGULATION OF CNS INFLAMMATION BY STROMAL CELLS different stromal cell types predict different properties of their pression of mesenchymal markers, such as a-smooth muscle barrier function. We focus on those CNS stromal cells that actin, platelet-derived growth factor receptor (PDGFR)-b, regulate immune cell entry into the CNS from the bloodstream and the chondroitin sulfate proteoglycan 4 (NG2) (18). A and control transition of inflammatory responses from regions continuous layer of VSMCs and pericytes ensheathes larger proximal to CNS barriers into the parenchyma (Fig. 1A). arteries and arterioles in the meninges and parenchyma Endothelial cells. In addition to delivering oxygen, nutrients, (Fig. 1A). This layer of smooth muscle cells becomes discon- and metabolites throughout the organ, BECs are a principal tinuous and eventually absent at the level of capillaries and constituent of the blood–brain barrier (BBB) and the blood– postcapillary venules (19). Consistent with the requirement cerebrospinal fluid barrier. With the exception of capillaries to maintain chemical stability in the CNS, the BBB vasculature that border the choroid plexus, brain BECs are unfenestrated has the highest pericyte coverage of any organ (20). Pericytes and tightly connected via intercellular tight junction proteins positioned at the interface of BBB endothelial cells and the glia and adhesion molecules that maintain the barrier function limitans were shown to regulate vascular permeability and instruct (13). The main conducting arteries of the brain stem form the astroglial endfeet polarization in a PDGFR-b–dependent manner external and internal carotid and vertebral arteries that bi- (21, 22). Moreover, under neuroinflammatory conditions, furcate at the Circle of Willis, traverse the meningeal surface pericytes may promote leukocyte migration into the CNS via of the CNS, and branch into the parenchyma. The BBB for upregulation of proinflammatory mediators and adhesion solutes is located uniquely at the level of capillaries (14). molecules, such as CXCL10, CXCL8, and ICAM1 (23, 24). Beyond the capillaries, the vascular tree widens again, tran- Intriguingly, a continuum in the phenotype and morphology of Downloaded from siting into postcapillary venules that ultimately rejoin men- arteriole VSMCs, BBB