Impact of X‐irradiation on microglia

Menzel, Franziska; Kaiser, Nicole; Haehnel, Susann; Rapp, Felicitas; Patties, Ina; Schöneberg, Nina; Haimon, Zhana; Immig, Kerstin; Bechmann, Ingo

doi:10.1002/glia.23239

Cited by 17 publications

(13 citation statements)

References 80 publications

(122 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data indicate that monocytes are capable of outcompeting endogenous CSF1Ri-resistant microglia under these conditions. Previous data has shown that microglia survive cranial irradiation, however do exhibit increased activation and decreased cell number [ 81 ], and that irradiation induces loss of proliferating cells, including progenitor/stem and microglial cells [ 60 ]. Thus, in order to induce complete monocyte engraftment, it appears that the brain must possess an empty microglial niche or microglial cells that lack the ability to proliferate/self-renew.…”

Section: Discussionmentioning

confidence: 99%

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Hohsfield

Najafi

Ghorbanian

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background Microglia, the primary resident myeloid cells of the brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in the CNS is of therapeutic interest. Methods Using whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e., monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS. Results Here, we identify a monocyte signature that includes an upregulation in Ccr1, Ms4a6b, Ms4a6c, Ms4a7, Apobec1, Lyz2, Mrc1, Tmem221, Tlr8, Lilrb4a, Msr1, Nnt, and Wdfy1 and a downregulation of Siglech, Slc2a5, and Ccl21a/b. We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain region-dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripherally derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits. Conclusions These findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Hohsfield

Najafi

Ghorbanian

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…We are beginning to recognize that activated microglia are also quite plastic cells that may differentiate into a plethora of subsets and perform various functions in response to different stimuli and environmental changes such as obesity, diet, alcohol, and even the host microbiota (Chunchai, Chattipakorn, & Chattipakorn, ; Erny et al, ; Hanamsagar & Bilbo, ; Henriques et al, ; Johnson, ; Mathys et al, ; Menzel et al, ). In support of this, it has recently been reported that microglia can even respond to microbial challenges during embryogenesis, and that the absent status of a microbiome has a quite different impact on both age‐ and sex‐specific microglial gene expression (Thion et al, ).…”

Section: Subsets Of Microglia: More Than Pro‐inflammatory and Immunormentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

View full text Add to dashboard Cite

Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

show abstract

“…However, a major caveat of this approach is that robust donor HSC engraftment requires the elimination of the host blood system by high doses of irradiation, upwards of 10 Gy (or 1,000 Rads). This can have long‐term effects on the brain environment, by activating microglia, modifying pathology and disrupting the blood brain barrier (BBB; Menzel et al, ). Moreover, a follow‐up study from the same group and others showed that shielding the head during irradiation to reduce BBB disruption, or use of parabiosis resulted in little to no contribution of bone marrow‐derived cells to the PAM population, despite robust bone marrow engraftment and donor peripheral immune cell reconstitution (Lampron, Lessard, & Rivest, ; Mildner et al, ; Wang et al, ).…”

Section: Introductionmentioning

confidence: 99%

CD11a expression distinguishes infiltrating myeloid cells from plaque‐associated microglia in Alzheimer's disease

Shukla

McIntyre

Marsh

et al. 2018

Glia

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the leading cause of age-related neurodegeneration and is characterized neuropathologically by the accumulation of insoluble beta-amyloid (Aβ) peptides. In AD brains, plaque-associated myeloid (PAM) cells cluster around Aβ plaques but fail to effectively clear Aβ by phagocytosis. PAM cells were originally thought to be brain-resident microglia. However, several studies have also suggested that Aβ-induced inflammation causes peripheral monocytes to enter the otherwise immune-privileged brain. The relationship between AD progression and inflammation in the brain remains ambiguous because microglia and monocyte-derived macrophages are extremely difficult to distinguish from one another in an inflamed brain. Whether PAM cells are microglia, peripheral macrophages, or a mixture of both remains unclear. CD11a is a component of the β2 integrin LFA1. We have determined that CD11a is highly expressed on peripheral immune cells, including macrophages, but is not expressed by mouse microglia. These expression patterns remain consistent in LPS-treated inflamed mice, as well as in two mouse models of AD. Thus, CD11a can be used as a marker to distinguish murine microglia from infiltrating peripheral immune cells. Using CD11a, we show that PAM cells in AD transgenic brains are comprised entirely of microglia. We also demonstrate a novel fluorescence-assisted quantification technique (FAQT), which reveals a significant increase in T lymphocytes, especially in the brains of female AD mice. Our findings support the notion that microglia are the lead myeloid players in AD and that rejuvenating their phagocytic potential may be an important therapeutic strategy. K E Y W O R D SAlzheimer's disease, CD11a, microglia, peripheral immune cells, plaque-associated myeloid cells

show abstract

Impact of X‐irradiation on microglia

Cited by 17 publications

References 80 publications

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

CD11a expression distinguishes infiltrating myeloid cells from plaque‐associated microglia in Alzheimer's disease

Contact Info

Product

Resources

About