Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS

Butovsky, Oleg; Siddiqui, Shafiuddin; Gabriely, Galina; Lanser, Amanda J.; Dake, Ben; Murugaiyan, Gopal; Doykan, Camille; Wu, Pauline M.; Gali, Reddy; Iyer, Lakshmanan K.; Lawson, Robert; Berry, James; Krichevsky, Anna M.; Cudkowicz, Merit; Weiner, Howard L.

doi:10.1172/jci62636

Cited by 420 publications

(498 citation statements)

References 82 publications

(103 reference statements)

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“…Collectively, these results provide compelling evidence that the phenotypic characteristics of the brain's myeloid component are altered substantially after SE, wherein myeloid cells that infiltrate the brain express high levels of Ly6C, a canonical marker of peripherally derived monocytes (37,38). Moreover, the appearance of Ly6C high CD11b + myeloid cells after SE is reliant on CCR2.…”

Section: Se (mentioning

confidence: 77%

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.

281

291

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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: Se (mentioning

confidence: 77%

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.

281

291

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“…5c), suggesting that the loss of Htr2b was associated with degeneration of mononuclear phagocytes in end stage SOD1(G86R) mice. To determine whether this degeneration of mononuclear phagocytes affected microglia and/or monocytes, we measured expression levels of genes known to be part of the homeostatic microglial signature [12,8,9,7], in particular Cx3cr1, Hexb, Tmem119, P2ry12, Olflm3 and SiglecH. All these genes displayed lower expression in SOD1(G86R) mice lacking the Htr2b gene than in SOD1(G86R) mice with the Htr2b gene (Fig.…”

Section: -Ht 2b Receptor Improves Microglial Survivalmentioning

confidence: 99%

“…An open question is whether the toxic effect of macrophages is mediated by resident microglia and/or by infiltrating blood monocytes. The extent of monocyte infiltration during ALS in mouse models remains controversial, with one study observing major monocytic infiltration [9], and others only very little if any [12,42,1,46]. Recently, genome-wide characterization of microglial and monocyte expression patterns led to the identification of a molecular signature of homeostatic microglia.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, microglia express genes not expressed in circulating monocytes or other resident tissue macrophages such as P2ry12, Hexb, Olfml3, SiglecH, Tgfbr1 or Tmem119 [8,48,31,12,7]. Contrastingly, monocytes express surface markers not present on microglia, such as Ly6c1 [9]. Importantly, microglia lose the expression of their homeostatic signature during disease progression [12,7], and develop unique expression patterns during experimental ALS distinct from inflammation-induced alteration [12,7].…”

Section: Introductionmentioning

confidence: 99%

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Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

et al. 2016

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Abstract:Microglia are the resident phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to overall increased phagocytic activity and production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in monocytes and microglia are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT 2B ), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT 2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT 2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT 2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT 2B mRNA in spinal cord and displayed less pronounced degeneration of mononuclear phagocytes than patients carrying two copies of the more common A allele. Thus functional 5-HT 2B receptors limit degeneration of spinal cord macrophages (most likely microglia), and slow disease progression in ALS. Targeting this receptor might be therapeutically useful.

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“…Regulatory T cells, which are reduced in patients with rapidly progressive ALS, may be a predictive marker [37,38]. miR-155 (i.e., micro-RNA), a promising marker of inflammation, is found to be upregulated in patients with ALS and may be predictive or prognostic [39][40][41]. These efforts will require concerted effort and considerable resources, but, if successful, will represent important new tools to speed ALS therapy development.…”

Section: Toward Novel Outcome Measures and Biomarkers In Als Trialsmentioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

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The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

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Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS

Cited by 420 publications

References 82 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

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

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