Increasing evidence suggests that macrophages critically shape brain homeostasis and disease.However, while the pivotal role of parenchymal microglia has gradually emerged, other brain-resident myeloid cells remain elusive. By dissecting border regions and combining single-cell RNA sequencing with high-dimensional cytometry, bulk RNA-sequencing, fate-mapping and microscopy, we reveal the remarkable diversity of non-parenchymal brain macrophages. Border-associated macrophages or BAMs residing in the dura mater, subdural meninges and choroid plexus consisted of distinct subsets that exhibited tissue-specific transcriptional signatures and underwent strong compositional changes during postnatal development. The gene regulatory networks of BAMs were identified and fundamentally differed from those of microglia. Importantly, we identified a unique non-homeostatic microglia-like population residing on the apical surface of the choroid plexus epithelium. Niche accessibility drove BAM ontogeny and determined whether embryonic macrophages were progressively replaced by bone marrow progenitors. Together, our work provides important insights into the biology of brain macrophages and offers a solid framework for future investigations.

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A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-κB activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies.