Role of Erk1/2 Signaling in the Regulation of Neutrophil Versus Monocyte Development in Response to G-CSF and M-CSF

Hu, Nan; Qiu, Yaling; Fan, Daiming

doi:10.1074/jbc.m115.668871

Cited by 17 publications

(20 citation statements)

References 51 publications

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“…Due to the biological coupling of the disc with the bone marrow, these pro-inflammatory and pro-osteoclastic genes can also directly exert their myelopoietic effects in the bone marrow. For instance, IL-6 activates myelopoiesis while suppressing erythopoiesis 19,30 , IL-4 governs T helper cell 2 differentiation and is a potent neutrophilic maturation factor 31 , CSF1 instructs hematopoietic stem cells to differentiate along the myeloid lineage and supports neutrophil differentiation 32,33 , and CCL2 recruits monocytes/macrophages and myeloid progenitors 34 . It is therefore not surprising that myelopoiesis is dysregulated in MC.…”

Section: Discussionmentioning

confidence: 99%

ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes

et al. 2017

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Study design Cross-sectional cohort analysis of patients with Modic Changes (MC). Objective Our goal was to characterize the molecular and cellular features of MC bone marrow and adjacent discs. We hypothesized that MC associate with biologic cross-talk between discs and bone marrow, the presence of which may have both diagnostic and therapeutic implications. Background Data MC are vertebral bone marrow lesions that can be a diagnostic indicator for discogenic low back pain. Yet, the pathobiology of MC is largely unknown. Methods Patients with Modic type 1 or 2 changes (MC1, MC2) undergoing at least 2-level lumbar interbody fusion with one surgical level having MC and one without MC (control level). Two discs (MC, control) and two bone marrow aspirates (MC, control) were collected per patient. Marrow cellularity was analyzed using flow cytometry. Myelopoietic differentiation potential of bone marrow cells was quantified to gauge marrow function, as was the relative gene expression profiles of the marrow and disc cells. Disc/bone marrow cross-talk was assessed by comparing MC disc/bone marrow features relative to unaffected levels. Results Thirteen MC1 and eleven MC2 patients were included. We observed pro-osteoclastic changes in MC2 discs, an inflammatory dysmyelopoiesis with fibrogenic changes in MC1 and MC2 marrow, and upregulation of neurotrophic receptors in MC1 and MC2 bone marrow and discs. Conclusion Our data reveal a fibrogenic and pro-inflammatory cross-talk between MC bone marrow and adjacent discs. This provides insight into the pain generator at MC levels and informs novel therapeutic targets for treatment of MC-associated LBP.

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Section: Discussionmentioning

confidence: 99%

ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes

et al. 2017

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“…This prompted us to investigate the mechanism of regulation of MTA1 transcription by G-CSF. Previous reports (33)(34)(35) have shown that c-Fos acts as a downstream effector transcription factor of STAT3 and MAPK signaling cascades upon G-CSF treatment. Sequence analysis of the MTA1 promoter revealed a putative c-Fos binding consensus sequence TGACT-CAC (36) at regions Ϫ2121 to Ϫ2114.…”

Section: Validation Of G-csf Effect In Acute Mptp Mousementioning

confidence: 93%

“…From the above results, it is clear that c-Fos is required for the G-CSF-induced activation of MTA1. Because c-Fos induction by G-CSF was reported to be mediated by the MAPK and STAT3 pathway (33)(34)(35), we looked at the activation status of both pathways and found that both pathways are activated upon G-CSF treatment (data not shown). Consistently, G-CSF failed to induce MTA1 promoter activity upon inhibiting STAT3 and MAPK pathways (data not shown).…”

Section: Validation Of G-csf Effect In Acute Mptp Mousementioning

confidence: 99%

Molecular Mechanism of Regulation of MTA1 Expression by Granulocyte Colony-stimulating Factor

Kumar

Jagadeeshan

Subramanian

et al. 2016

Journal of Biological Chemistry

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Parkinson disease (PD) is a neurodegenerative disorder with loss of dopaminergic neurons of the brain, which results in insufficient synthesis and action of dopamine. Metastasis-associated protein 1 (MTA1) is an upstream modulator of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and hence MTA1 plays a significant role in PD pathogenesis. To impart functional and clinical significance to MTA1, we analyzed MTA1 and TH levels in the substantia nigra region of a large cohort of human brain tissue samples by Western blotting, quantitative PCR, and immunohistochemistry. Our results showed that MTA1 and TH levels were significantly down-regulated in PD samples as compared with normal brain tissue. Correspondingly, immunohistochemistry analysis for MTA1 in substantia nigra sections revealed that 74.1% of the samples had a staining intensity of <6 in the PD samples as compared with controls, 25.9%, with an odds ratio of 8.54. Because of the clinical importance of MTA1 established in PD, we looked at agents to modulate MTA1 expression in neuronal cells, and granulocyte colony-stimulating factor (G-CSF) was chosen, due to its clinically proven neurogenic effects. Treatment of the human neuronal cell line KELLY and acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model with G-CSF showed significant induction of MTA1 and TH with rescue of phenotype in the mouse model. Interestingly, the observed induction of TH was compromised on silencing of MTA1. The underlying molecular mechanism of MTA1 induction by G-CSF was proved to be through induction of c-Fos and its recruitment to the MTA1 promoter. Parkinson disease (PD)4 is an idiopathic degenerative disorder of the central nervous system characterized by slow and decreased movement, pill-rolling tremor, and postural instability, and it is primarily caused by dopamine deficiency (1, 2). The rate-limiting enzyme for dopamine synthesis is tyrosine hydroxylase (TH) (3). Currently, there is no cure for PD, and patients are usually given drugs that provide symptomatic relief (4). Recently, it was shown that G-CSF enhances recovery in the mouse model of PD, and hence the G-CSF receptor might be a novel target for modifying the disease process in PD (5, 6). It is well documented that a consistent abnormality in PD is degeneration of dopaminergic neurons in SN leading to a reduction of striatal dopamine levels (7). TH catalyzes the formation of L-hydroxyphenylalanine, the rate-limiting step in the biosynthesis of dopamine. Thus, efficient treatment strategy for PD could be based on correcting or bypassing the TH enzyme deficiency or its downstream enzymes essential for catecholamine synthesis (8). For this, elucidation of the molecular mechanism of human TH gene regulation is very essential. Also, epigenetic profiling of the human TH promoter suggests that chromatin remodeling could have a significant impact in conferring tissue-specific gene expression of the human TH gene (9); however, its specific role in TH transcription remains poorly understood...

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“…18 A potential signaling pathway downstream of SFKs involved in lineage choice is the MEK/ERK pathway. 37,38 It has previously been shown that Y559 activates SFK and MEK/ERK signaling in Ms. 18 To test whether ERK is activated through Y559(/807) in primary progenitors, we performed phospho-flow with Csf1r 2/2 ivGMPs expressing Ywt, YEF, Y559AB, or Y559/807AB. Stimulation with CSF-1 led to ERK activation with both AB mutants and could be blocked using an SFK inhibitor, demonstrating that Y559 signals through MEK/ERK via SFKs ( Figure 5A-B).…”

Section: Y559 Signals Via Sfk-mek/erkmentioning

confidence: 99%

CSF-1–induced Src signaling can instruct monocytic lineage choice

Endele

Loeffler

Kokkaliaris

et al. 2017

Blood

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Controlled regulation of lineage decisions is imperative for hematopoiesis. Yet, the molecular mechanisms underlying hematopoietic lineage choices are poorly defined. Colony-stimulating factor 1 (CSF-1), the cytokine acting as the principal regulator of monocyte/macrophage (M) development, has been shown to be able to instruct the lineage choice of uncommitted granulocyte M (GM) progenitors toward an M fate. However, the intracellular signaling pathways involved are unknown. CSF-1 activates a multitude of signaling pathways resulting in a pleiotropic cellular response. The precise role of individual pathways within this complex and redundant signaling network is dependent on cellular context, and is not well understood. Here, we address which CSF-1-activated pathways are involved in transmitting the lineage-instructive signal in primary bone marrow-derived GM progenitors. Although its loss is compensated for by alternative signaling activation mechanisms, Src family kinase (SFK) signaling is sufficient to transmit the CSF-1 lineage instructive signal. Moreover, c-Src activity is sufficient to drive M fate, even in nonmyeloid cells.

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Role of Erk1/2 Signaling in the Regulation of Neutrophil Versus Monocyte Development in Response to G-CSF and M-CSF

Cited by 17 publications

References 51 publications

ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes

ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes

Molecular Mechanism of Regulation of MTA1 Expression by Granulocyte Colony-stimulating Factor

CSF-1–induced Src signaling can instruct monocytic lineage choice

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