Trafficking CD11b-Positive Blood Cells Deliver Therapeutic Genes to the Brain of Amyloid-Depositing Transgenic Mice

Lebson, Lori; Nash, Kevin; Kamath, Siddharth G.; Herber, Donna L.; Carty, Nikisha; Lee, Daniel; Li, Qingyou; Szekeres, Károly; Jinwal, Umesh K.; Koren, John; Dickey, Chad A.; Gottschall, Paul E.; Morgan, Dave; Gordon, Marcia N.

doi:10.1523/jneurosci.0329-10.2010

Cited by 110 publications

(131 citation statements)

References 39 publications

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“…Blood-borne monocytes have been shown to infiltrate damaged or diseased brain tissue in animal models of other human neurological disease, such as the EAE model of multiple sclerosis (35), Alzheimer's disease (27,28,44), and traumatic brain injury (13,45). Previous studies have also reported elevated numbers of peripheral immune leukocytes after epileptiform activity (46,47).…”

Section: Discussionmentioning

confidence: 99%

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Varvel

Neher

Bosch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

263

269

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The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs. brain-infiltrating monocytes. Chemokine receptor 2 (CCR2 + ) monocytes invade the hippocampus between 1 and 3 d after SE. In contrast, only an occasional CD3 + T lymphocyte was encountered 3 d after SE. The initial cellular sources of the chemokine CCL2, a ligand for CCR2, included perivascular macrophages and microglia. The induction of the proinflammatory cytokine IL-1β was greater in FACS-isolated microglia than in brain-invading monocytes. However, Ccr2 knockout mice displayed greatly reduced monocyte recruitment into brain and reduced levels of the proinflammatory cytokine IL-1β in hippocampus after SE, which was explained by higher expression of the cytokine in circulating and brain monocytes in wild-type mice. Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage. Our findings identify brain-infiltrating monocytes as a myeloid-cell subclass that contributes to neuroinflammation and morbidity after SE. Inhibiting brain invasion of CCR2 + monocytes could represent a viable method for alleviating the deleterious consequences of SE. myeloid cell heterogeneity | epileptogenesis | neuroprotection | seizure | microgliosis S tatus epilepticus (SE) is a serious medical emergency that triggers a series of cellular and molecular events that can result in the development of epilepsy, a chronic neurological disorder characterized by a persistently lowered seizure threshold (1). The early consequences of SE in rodents include a robust neuroinflammatory response, selective neuronal degeneration, and transient opening of the blood-brain barrier (BBB), leading to later cognitive decline. Although the neuroinflammatory features of SE in man are less well known, extravasation of albumin into the brain was observed for patients who died in SE (2), elevated cerebrospinal fluid levels of the cytokines IL-6, IL-8, and CXCL10 are typically found in patients with refractory SE compared with patients with other inflammatory neurologic disorders (3), and intense gliosis (both astrocytes and microglia) was observed in the temporal cortex of a patient with new-onset focal seizures that progressed to refractory SE (4). These admittedly sparse clinical findings are consistent with the much more extensive animal literature in demonstrating a florid inflammatory response of the brain to SE (5). We and others have provided evidence in animal models of epilepsy that quenching inflamma...

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Section: Discussionmentioning

confidence: 99%

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Varvel

Neher

Bosch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

263

269

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“…This is relevant for myeloid cell-based gene therapy in AD. In fact, infusion of millions of genetically engineered BM-derived CD11b ϩ cells into APP swe/PS1 transgenic mice resulted in some parenchymal myeloid cell engraftment and modulation of amyloid deposition (Lebson et al, 2010). The impact of gene therapeutic approaches using myeloid precursors for CNS diseases has been highlighted in a mouse model of metachromatic leukodystrophy (Biffi et al, 2004), and more recently, in children with X-linked adrenoleukodystrophy (Cartier et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Distinct and Non-Redundant Roles of Microglia and Myeloid Subsets in Mouse Models of Alzheimer's Disease

Mildner¹,

Schlevogt²,

Kierdorf³

et al. 2011

J. Neurosci.

292

261

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Mononuclear phagocytes are important modulators of Alzheimer's disease (AD), but the specific functions of resident microglia, bone marrow-derived mononuclear cells, and perivascular macrophages have not been resolved. To elucidate the spatiotemporal roles of mononuclear phagocytes during disease, we targeted myeloid cell subsets from different compartments and examined disease pathogenesis in three different mouse models of AD (APP swe/PS1 , APP swe , and APP23 mice). We identified chemokine receptor 2 (CCR2)-expressing myeloid cells as the population that was preferentially recruited to ␤-amyloid (A␤) deposits. Unexpectedly, AD brains with dysfunctional microglia and devoid of parenchymal bone marrow-derived phagocytes did not show overt changes in plaque pathology and A␤ load. In contrast, restriction of CCR2 deficiency to perivascular myeloid cells drastically impaired ␤-amyloid clearance and amplified vascular A␤ deposition, while parenchymal plaque deposition remained unaffected. Together, our data advocate selective functions of CCR2-expressing myeloid subsets, which could be targeted specifically to modify disease burden in AD.

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“…Additionally, in AD mouse models, bone marrow-derived macrophages have been shown to limit plaque growth (45) and genetically modified monocytes can modulate AD pathology (46). Importantly, microglial apoptosis has been implicated in X-linked adrenoleukodystrophy (ALD) (21), and beneficial clinical outcomes have been reported in ALD patients subject to therapies using nonmutant myeloid cells (47).…”

Section: Discussionmentioning

confidence: 99%

Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells

Varvel

Grathwohl

Baumann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

210

196

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Under most physiological circumstances, monocytes are excluded from parenchymal CNS tissues. When widespread monocyte entry occurs, their numbers decrease shortly after engraftment in the presence of microglia. However, some disease processes lead to focal and selective loss, or dysfunction, of microglia, and microglial senescence typifies the aged brain. In this regard, the long-term engraftment of monocytes in the microglia-depleted brain remains unknown. Here, we report a model in which a niche for myeloid cells was created through microglia depletion. We show that microglia-depleted brain regions of CD11b-HSVTK transgenic mice are repopulated with new Iba-1-positive cells within 2 wk. The engrafted cells expressed high levels of CD45 and CCR2 and appeared in a wave-like pattern frequently associated with blood vessels, suggesting the engrafted cells were peripheral monocytes. Although two times more numerous and morphologically distinct from resident microglia up to 27 wk after initial engraftment, the overall distribution of the engrafted cells was remarkably similar to that of microglia. Two-photon in vivo imaging revealed that the engrafted myeloid cells extended their processes toward an ATP source and displayed intracellular calcium transients. Moreover, the engrafted cells migrated toward areas of kainic acid-induced neuronal death. These data provide evidence that circulating monocytes have the potential to occupy the adult CNS myeloid niche normally inhabited by microglia and identify a strong homeostatic drive to maintain the myeloid component in the mature brain.chemokines | myeloid cell heterogeneity | neuroinflammation | in vivo calcium imaging

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Trafficking CD11b-Positive Blood Cells Deliver Therapeutic Genes to the Brain of Amyloid-Depositing Transgenic Mice

Cited by 110 publications

References 39 publications

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Distinct and Non-Redundant Roles of Microglia and Myeloid Subsets in Mouse Models of Alzheimer's Disease

Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells

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