Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia

Cronk, James C.; Filiano, Anthony J.; Louveau, Antoine; Marin, Ioana; Marsh, Rachel; Ji, Emily; Goldman, Dylan H.; Smirnov, Igor; Geraci, Nicholas S.; Acton, Scott T.; Overall, Christopher C.; Kipnis, Jonathan

doi:10.1084/jem.20180247

Cited by 295 publications

(335 citation statements)

References 78 publications

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“…Here, we show that repopulated microglia display high expression of both TMEM119 and P2RY12 (Figure 2k–n), demonstrating that repopulated microglia are indeed resident microglia and do not originate from peripherally‐derived myeloid cells. These findings are in line with previous studies from our laboratory (Elmore et al, 2014) and others (Cronk et al, 2018; Huang et al, 2018) showing that repopulating microglia are CNS‐derived and not from peripheral infiltrates. Thus, CSF1R inhibitor‐directed replacement of microglia in the aged brain restores age‐induced changes in microglial numbers, morphologies, and CD68 puncta, reverting the microglial phenotype to that observed in the young brain, at least out to 28 days.…”

Section: Resultssupporting

confidence: 92%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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Section: Resultssupporting

confidence: 92%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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“…For example, other models of microglia depletion using genetic approaches have described a slower mechanism of repopulation that derives from peripheral cells (Varvel et al 2012). Furthermore, continuous tamoxifen-induced genetic CSF1R deletion in microglia leads to chronic partial microglial depletion, which over time causes the brain to partly (~50%) fill with peripherally derived macrophages that take up residence within the brain parenchyma (Cronk et al 2018). Although our previous studies have shown that with a single “normal” repopulation event following CSF1R inhibition (Elmore et al 2014), peripherally derived cells do not infiltrate into the brain, it is yet to be determined whether peripherally derived cells contribute to the myeloid cell repopulation in either of the extended repopulation events detailed here.…”

Section: Discussionmentioning

confidence: 99%

A limited capacity for microglial repopulation in the adult brain

Najafi

Crapser

Jiang

et al. 2018

Glia

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Microglia are the resident immune cell of the central nervous system (CNS), and serve to protect and maintain the local brain environment. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R); administration of CSF1R inhibitors that cross the blood brain barrier (BBB) lead to the elimination of up to 99% of microglia, depending on CNS exposure and treatment duration. Once microglia are depleted, withdrawal of inhibitor stimulates repopulation of the entire CNS with new cells, conceivably enabling a therapeutic strategy for beneficial renewal of the entire microglial tissue. We have explored the kinetics and limits of this repopulation event and show that the rate of microglial repopulation is proportional to the extent of microglial depletion – greater depletion of microglia results in more rapid repopulation. Using a CSF1R inhibitor formulation that eliminates ~99% of microglia within 7 days, we subjected mice to multiple rounds of elimination (7 days’ treatment) and repopulation (7 days’ recovery) and found that the brain only has the capacity for a single complete repopulation event; subsequent elimination and CSF1R inhibitor withdrawal fail to repopulate the brain. However, if the recovery time between, or after, cycles is extended sufficiently then the brain can ultimately repopulate. These kinetic studies define the opportunities and possible limits of the remarkable renewal capacities of microglia.

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“…In agreement, we found that when we applied a lethal irradiation, there is a significant engraftment of circulating cells (GFP + ) into the spinal cord of animals, even prior to SNI induction. Furthermore, besides BBB disruption there is evidence indicating that irradiation induces CNS resident cell death, especially microglia, which could cause leukocyte migration into the spinal cord in response to several inflammatory mediators released in the tissue . In this context, the increase in the number of GFP + cells in the spinal cord after SNI is simple explained by the fact that GFP + cells that engrafted after irradiation cells start to proliferate .…”

Section: Discussionmentioning

confidence: 99%

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

Guimarães

Davoli‐Ferreira

Fonseca

et al. 2019

Journal of Leukocyte Biology

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The development of neuropathic pain after peripheral nerve injury involves neuroimmune–glial interactions in the spinal cord. However, whether the development of neuropathic pain depends on the infiltration of peripheral immune cells, such as monocytes, into the spinal cord parenchyma after peripheral nerve damage remains unclear. Here, we used a combination of different techniques such as transgenic reporter mouse (Cx3cr1GFP/+ and Ccr2RFP/+ mice), bone marrow chimeric mice, and parabiosis to investigate this issue in spared nerve injury (SNI) model. Herein, we provided robust evidence that, although microglial cells are activated/proliferate at the dorsal horn of the spinal cord after SNI, peripheral hematopoietic cells (including monocytes) are not able to infiltrate into the spinal cord parenchyma. Furthermore, there was no evidence of CCR2 expression in intrinsic cells of the spinal cord. However, microglial cells activation/proliferation in the spinal cord and mechanical allodynia after SNI were reduced in Ccr2‐deficient mice. These results suggest that blood‐circulating leukocytes cells are not able to infiltrate the spinal cord parenchyma after distal peripheral nerve injury. Nevertheless, they indicate that CCR2‐expressing cells might be indirectly regulating microglia activation/proliferation in the spinal cord after SNI. In conclusion, our study supports that CCR2 inhibition could be explored as an interventional approach to reduce microglia activation and consequently neuropathic pain development after peripheral nerve injury.

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Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia

Abstract: Peripherally derived macrophages can engraft the brain in the context of chronic microglia loss without brain irradiation and maintain a unique transcriptional signature throughout different experimental contexts.

Cited by 295 publications

References 78 publications

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

A limited capacity for microglial repopulation in the adult brain

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

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