Dendritic Cells and Microglia Have Non-redundant Functions in the Inflamed Brain with Protective Effects of Type 1 cDCs.

Brain CD11c+ cells share features with microglia and dendritic cells (DCs). Sterile inflammation increases brain CD11c+ cells, but their phenotype, origin, and functions remain largely unknown. We report that, after cerebral ischemia, microglia attract DCs to the inflamed brain, and astroglia produce Flt3 ligand, supporting development and expansion of CD11c+ cells. CD11c+ cells in the inflamed brain are a complex population derived from proliferating microglia and infiltrating DCs, including a major subset of OX40L+ conventional cDC2, and also cDC1, plasmacytoid, and monocyte-derived DCs. Despite sharing certain morphological features and markers, CD11c+ microglia and DCs display differential expression of pattern recognition receptors and chemokine receptors. DCs excel CD11c- and CD11c+ microglia in the capacity to present antigen through MHCI and MHCII. Of note, cDC1s protect from brain injury after ischemia. We thus reveal aspects of the dynamics and functions of brain DCs in the regulation of inflammation and immunity.This work was funded by Ministerio de Ciencia, Innovacion y Universidades (MICINN) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) (SAF2017-87459-R), the European Union (EU) (H2020-ITN-2018-813294-ENTRAIN), and Fundacio Marato TV3 (201723 to A.M.P. and D.S.). Work in the D.S. laboratory is funded by Centro Nacional de Investigaciones Cardiovasculares (CNIC), the European Research Council (ERC-2016-Consolidator Grant 725091), the EU (635122-PROCROP H2020), and MICINN-FEDER (SAF2016-79040-R). The EU (FP7-PEOPLE-2013-ITN-n 07962) supported M. Gallizioli. The PERIS program of Generalitat de Catalunya supported F.M.-M. A.O.-d.-A. had a fellowship from MICINN-FPI (BES-2015-074419). C.d.F. is supported by the AECC Foundation (INVES192DELF).S