Camille E. Doykan

Identification of a unique TGF-β–dependent molecular and functional signature in microglia

Microglia are myeloid cells of the CNS that participate both in normal CNS function and in disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia versus myeloid and other immune cells. Of the 239 genes, 106 were enriched in microglia as compared with astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS, and was also observed in human microglia. We found that TGF-β was required for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia and that microglia were absent in the CNS of TGF-β1–deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling and provide insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.

Differential roles of microglia and monocytes in the inflamed central nervous system

Phagocytic monocyte-derived macrophages associate with the nodes of Ranvier and initiate demyelination while microglia clear debris and display a suppressed metabolic gene signature in EAE.

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

Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We also found a decrease in resident microglia in the spinal cord with disease progression. Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2. As disease onset neared, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS by spinal cord-derived microglia. Treatment with anti-Ly6C mAb modulated the Ly6Chi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival. In humans with ALS, the analogous monocytes (CD14+CD16-) exhibited an ALS-specific microRNA inflammatory signature similar to that observed in the ALS mouse model, linking the animal model and the human disease. Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach.

Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice.

To investigate miR‐155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).

REMOVED: Identification of a unique molecular and functional microglia signature in health and disease

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Targeting miR-155 restores dysfunctional microglia and ameliorates disease in the SOD1 model of ALS

This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our‐business/policies/article‐withdrawal)

Corrigendum: Identification of a unique TGF-β–dependent molecular and functional signature in microglia

Corrigendum: Identification of a unique TGF-β–dependent molecular and functional signature in microglia

Dysregulation of the APOE-TGFb pathway leads to loss of the microglial homeostatic signature in neurologic diseases including MS, ALS and AD

the disease. We are now interested in translating these findings to the human system. Therefore, we analyzed human Th17 cells in MS patients and healthy persons. Furthermore, we established Th17 cultures from human peripheral blood mononuclear cells (PBMCs). Methods: Cytokine producers were analyzed in patients with a highly active disease (treated with fingolimod or natalizumab) and ageand sex-matched controls. PBMCs were isolated from the blood of both natalizumab-treated patients and healthy donors via gradient density centrifugation. The cells were stimulated for 4 h and a magnetic bead based IL-17 secretion assay was performed on the cells. The cells were cultured and enriched for 6 days and characterized or co-cultured with either murine or human neurons for 24 h. The cell death rate was determined via TUNEL staining. Results: The cytokine profiles of 40 patients treated with natalizumab show very significant differences in lymphocyte numbers and cytokines compared to healthy donors. While natalizumab-treated patients show higher lymphocyte numbers and larger absolute amounts of IL-17 producing cells per milliliter of blood, only very few lymphocytes in fingolimod-treated patients were detectable. Ex vivo derived Th17 cells could be successfully expanded in vitro. Th17 cultures from patients and healthy controls showed similarly stable IL-17 expression concomitant with the cytokines IFN-γ, IL-22 and IL-4. The pathogenicity of these cells were analyzed in different cellular assays and compared with control T cells. Furthermore, Th17 absolute numbers were correlated with disease activity and MRI data in patients after stopping therapy with natalizumab. Conclusion: Differences in cytokine profiles and numbers in the patient group versus controls could be shown. Higher IL-17 producer numbers in natalizumab-treated patients suggest that Th17 cells are sequestered in the blood.

Erratum: Identification of a unique TGF-β-dependent molecular and functional signature in microglia (Nature Neuroscience (2014) 17 (131-143))

Corrigendum: Identification of a unique TGF-β–dependent molecular and functional signature in microglia

Erratum: Corrigendum: Identification of a unique TGF-β–dependent molecular and functional signature in microglia

Corrigendum: Identification of a unique TGF-β–dependent molecular and functional signature in microglia