Peripheral nerve resident macrophages are microglia-like cells with tissue-specific programming

Abstract

Whereas microglia are recognized as fundamental players in central nervous system 16 (CNS) development and function, much less is known about macrophages of the peripheral nervous 17 system (PNS). Here we show that self-maintaining PNS macrophages share unique features with 18 CNS microglia. By comparing gene expression across neural and conventional tissue-resident 19 macrophages, we identified transcripts that were shared among neural resident macrophages as 20 well as selectively enriched in PNS macrophages. Remarkably, PNS macrophages constitutively 21 expressed genes previously identified to be upregulated by activated microglia during aging or 22 neurodegeneration. Several microglial activation-associated and PNS macrophage-enriched genes 23 were also expressed in spinal cord microglia at steady state. While PNS macrophages arose from 24 both embryonic and hematopoietic precursors, their expression of activation-associated genes did 25 not differ by ontogeny. Collectively, these data uncover shared and unique features between neural 26 resident macrophages and emphasize the role of nerve environment for shaping PNS macrophage 27 identity. 283 Introduction: The significant role of resident neural macrophages in neuroinflammation and disease 29 progression is increasingly appreciated in mouse models and individuals with neurodegeneration (1, 30 2, 3). Such advances, which largely rely on the interpretation of data from transcriptional analyses 31 and human genome-wide association studies (GWAS) of Alzheimer's Disease (AD) and other 32 neurodegenerative conditions, have led to critical findings about cellular and molecular processes 33 underlying such diseases (4, 5, 6). Most of these studies, however, have focused on resident 34 macrophages in the brain (microglia) and, to a lesser extent, the spinal cord. Meanwhile, the 35 transcriptional identity and functions of resident macrophages in the PNS remain mostly unknown. 36The PNS consists of a multitude of neuronal networks that relay motor and sensory 37 information between the CNS and the rest of the body (7). Though it has the capacity to regenerate, 38 the PNS is also prone to injury and degeneration (8). Studies of PNS injury have shown that PNS 39 macrophages play important roles for debris clearance, pain development, and regeneration (9, 10, 40 11). While the contribution of recruited monocytes cannot be excluded, these studies demonstrate 41 the importance of PNS macrophages in nerve injury. Understanding the roles of these cells in 42 homeostasis and disease may be broadly beneficial for resolving neuroinflammation. 43In addition to monocyte-derived macrophages in nerve injury, there are also resident 44 macrophages in the PNS at steady state (12, 13). While their residence in neuronal tissues is 45 inherently microglia-like, PNS macrophages exist within a unique peripheral nerve 46 microenvironment. Moreover, though it is known that CNS microglia are derived from the yolk sac 47 during embryogenesis and depend on IL-34 for development (14, 15), the ...

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Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain

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