The role of TAM family receptors and ligands in the nervous system: From development to pathobiology

Shafit‐Zagardo, Bridget; Gruber, Ross C.; DuBois, Juwen C.

doi:10.1016/j.pharmthera.2018.03.002

Cited by 66 publications

(56 citation statements)

References 266 publications

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“…These findings are well in line with previous observations. Noteworthy, the ectodomains of these receptors are released upon cleavage by sheddases like ADAM10 and ADAM17, and conditions of shedding as well as the function of the soluble ectodomains are incompletely understood . The shedded receptors can have antagonistic function or act as signal mediators.…”

Section: Discussionmentioning

confidence: 99%

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Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study

Brosseron¹,

Kolbe²,

Santarelli³

et al. 2020

Alzheimer's & Dementia

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Introduction: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY.Methods: A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published.Results: Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors.Discussion: Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

“…Though many typical proinflammatory proteins are hard to detect in the CSF of dementia subjects, research has nonetheless led to several immunity markers that can be reliably analysed and therefore constitute reasonable candidates for functional neuroinflammation panels. 2,[9][10][11][12][13] This study aimed to verify observations for 21…”

Section: Introductionmentioning

confidence: 95%

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study

Brosseron¹,

Kolbe²,

Santarelli³

et al. 2020

Alzheimer's & Dementia

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“…Although the implication of several signalling pathways involved in the modulation of CX3CL1 actions has been described (Al-Aoukaty, Rolstad et al, 1998, Sheridan & Murphy, 2013, such as PI3K/AKT , Lyons, Lynch et al, 2009), most of the data were obtained in neuronal cell types (Sheridan & Murphy, 2013). Therefore, we investigated what signalling pathways could be activated by CX3CL1 when we used a kinase proteome profiler assay ( Figure 2A) in immortalized microglia (IMG) cells treated with CX3CL1 (100 nM) for 1 h. Interestingly, the results indicate that CX3CL1 treatment induced the activation of three members of MAPK: extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) ( Figure 2B).…”

Section: B Signalling Activationmentioning

confidence: 99%

Impaired Signaling of NF-κB and NRF2 in CX3CR1-Deficient Microglia: Implications in Tauopathies

Castro-Sánchez

García-Yagüe

Kügler

et al. 2018

Preprint

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“…In animal models, MerTK and its cognate ligand, Gas6, have shown to play protective roles, particularly in the cuprizone toxin model where Gas6-knockout mice develop a more severe level of demyelination coupled with a delayed remyelination process (35). Experimental evidence strongly supports a functional role for MerTK in inflammation resolution, debris clearance, and repair (36).…”

Section: Discussionmentioning

confidence: 94%

Vitamin D regulates MerTK-dependent phagocytosis in human myeloid cells

Clarke

Yaqubi

Futhey

et al. 2020

Preprint

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Vitamin D deficiency is a major environmental risk factor for the development of multiple 1 sclerosis (MS). The major circulating metabolite of vitamin D (25OHD) is converted to the 2 active form (calcitriol) by the hydroxylase enzyme CYP27B1. In MS lesions the tyrosine kinase 3MerTK expressed by microglia and macrophages regulates phagocytosis of myelin debris and 4 apoptotic cells that can accumulate and inhibit tissue repair and remyelination. We show that 5 calcitriol downregulates MerTK mRNA and protein expression in adult human microglia and 6 monocyte-derived macrophages, thereby inhibiting myelin phagocytosis and apoptotic cell 7 clearance. Proinflammatory myeloid cells express high levels of CYP27B1 compared to 8 homeostatic (TGFβ-treated) myeloid cells. Only proinflammatory cells in the presence of TNF-α 9 generate calcitriol from 25OHD, resulting in repression of MerTK expression and function. The 10 selective production of calcitriol in proinflammatory myeloid cells leading to downregulation of 11 MerTK-mediated phagocytosis has the potential to reduce the risk for auto-antigen presentation 12 while retaining the phagocytic ability of homeostatic myeloid cells, thereby contributing to 13 inflammation reduction and enhanced tissue repair. 14 cuprizone model of demyelination (7). MDMs derived from MS patients show impaired ability 38 to phagocytose myelin, a defect linked to a reduction in MerTK expression (8). In addition to 39 clearing myelin debris, MerTK mediates the process of efferocytosis, the removal of dead/dying 40 cells, which is important for autoreactive T-cell fate determination in MS (9). The functions of 41 myeloid cells are dependent on their state of activation. TGFβ, a key cytokine involved in CNS 42 homeostasis, has been shown to maintain cells in a homeostatic state characterized by high 43 expression of MerTK, TREM2, CSF1R and Mafb (10). In contrast, MerTK expression is 44 comparatively lower in proinflammatory myeloid cells, a population shown to contribute to MS 45 pathogenesis (6). Genome-wide association studies (GWAS) have explained much of MS 46 heritability. Single nucleotide polymorphisms (SNPs) in CYP24A1 and CYP27B1, which tightly 47 Methods 61Monocyte-derived macrophages -Human peripheral blood mononuclear cells (PBMCs) were 62 isolated from healthy donors by Ficoll-Hypaque density gradient centrifugation (GE healthcare). 63Monocytes were isolated from PBMCs using magnetic CD14+ isolation beads (Miltenyi). 64Proinflammatory (MØ GMcsf ) and alternative (M2) macrophages were generated by differentiating 65 monocytes for 6 days in the presence of 25ng/mL GM-CSF and M-CSF respectively. To 66 generate CNS homeostatic (MØ 0 ) macrophages, TGFβ (50ng/mL) was added to the M-CSF 67 culture conditions on days 3 and 6. 10 -7 M calcitriol (Selleckchem) was added to designated 68 macrophages on day 1 of culture and maintained throughout differentiation. Culture media was 69 replenished every 2-3 days. 70Microglia & astrocytes -Human adult microglia were isolated from brain tissue of ...

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The role of TAM family receptors and ligands in the nervous system: From development to pathobiology

Cited by 66 publications

References 266 publications

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study

Impaired Signaling of NF-κB and NRF2 in CX3CR1-Deficient Microglia: Implications in Tauopathies

Vitamin D regulates MerTK-dependent phagocytosis in human myeloid cells

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