GO:1902227 negative regulation of macrophage colony-stimulating factor signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902227 describes any process that stops, prevents, or reduces the frequency, rate, or extent of macrophage colony-stimulating factor (M-CSF/CSF1) signaling [1,4].
• M-CSF signaling is initiated by CSF1 binding to CSF1R, a receptor tyrosine kinase that drives monocyte/macrophage survival, proliferation, and differentiation.
• Negative regulation of this pathway is critical for resolving inflammation and preventing pathological macrophage accumulation in cancer and fibrosis [2,3,7].
• Key negative regulators include microRNAs such as miR-148b, heterotrimeric Gi2 proteins, and cytokine signaling suppressors like SOCS proteins [3,4,7].
• Dysregulated M-CSF signaling is implicated in tumor-associated macrophage infiltration, hepatocellular carcinoma metastasis, and maladaptive cardiac remodeling [2,3].
• CRISPR knockout, knock-in, and overexpression models enable precise dissection of negative regulators within this pathway [1,5].
Description
Macrophage colony-stimulating factor (M-CSF, also known as CSF1) is a cytokine that governs the survival, proliferation, and differentiation of mononuclear phagocytes. The signaling pathway triggered by M-CSF binding to its receptor CSF1R is essential for innate immunity and tissue homeostasis, but its excessive or prolonged activation contributes to chronic inflammation, tumor progression, and fibrosis [2,3]. GO:1902227, negative regulation of macrophage colony-stimulating factor signaling pathway, encompasses the cellular processes that attenuate or terminate this signaling cascade [1,4]. Understanding these negative regulatory mechanisms is fundamental for researchers aiming to modulate macrophage activity in disease settings. This article integrates authoritative QuickGO annotation data with verified PubMed literature to provide a research-grade overview of the genes, mechanisms, and experimental models relevant to GO:1902227.
negative regulation of macrophage colony-stimulating factor signaling pathway At A Glance
| GO ID | GO:1902227 |
|---|---|
| GO term | negative regulation of macrophage colony-stimulating factor signaling pathway |
| Ontology | biological_process |
| Synonym | inhibition of M-CSF signaling pathway; downregulation of macrophage colony-stimulating factor signaling pathway |
| Major function | Attenuation or termination of M-CSF/CSF1-induced intracellular signaling |
| Related receptor | CSF1R (colony-stimulating factor 1 receptor) |
| Key negative regulators | miR-148b, Gi2 proteins, SOCS proteins, Sipa1 |
| Associated diseases | Hepatocellular carcinoma, myocardial infarction, chronic inflammation |
What Is GO:1902227?
GO:1902227 is a biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of the macrophage colony-stimulating factor signaling pathway. In practical terms, it includes molecular events such as receptor downregulation, dephosphorylation of signaling intermediates, induction of inhibitory proteins, and microRNA-mediated suppression of pathway components [3,4,7].
Why Is negative regulation of macrophage colony-stimulating factor signaling pathway Important in Cell Biology?
Negative regulation of M-CSF signaling is essential for preventing excessive macrophage activation and accumulation, which underlies numerous pathological conditions including cancer metastasis, cardiac fibrosis, and chronic inflammatory diseases [2,3,7]. Therapeutic strategies that enhance or mimic these negative regulatory mechanisms could reduce tumor-associated macrophage infiltration and improve outcomes in hepatocellular carcinoma and other malignancies. Conversely, loss of negative regulation can drive maladaptive fibroblast-myeloid crosstalk after myocardial infarction. Thus, GO:1902227 represents a critical control point for macrophage-centered immune modulation.
• Controls macrophage survival and proliferation by limiting CSF1R signaling duration.
• Prevents chronic inflammation by terminating cytokine-driven myeloid cell expansion.
• Regulates tumor-associated macrophage infiltration in hepatocellular carcinoma.
• Modulates maladaptive fibroblast-myeloid axis after myocardial infarction.
• Involves microRNA-mediated suppression, e.g., miR-148b targeting CSF1 signaling.
• Heterotrimeric Gi2 proteins regulate M-CSF-induced proliferation, providing a negative feedback node.
• Dysregulation contributes to breast cancer microenvironment remodeling via hypoxia-inducible factors.
• Provides targets for CRISPR-based functional genomics in immuno-oncology [1,5].
• Essential for resolving inflammation through SOCS-mediated cytokine signaling suppression.
• Offers experimental entry points for point-mutation and knock-in studies of CSF1R signaling.
What Happens During negative regulation of macrophage colony-stimulating factor signaling pathway?
Receptor-level attenuation
In simple terms: The cell reduces the number or activity of M-CSF receptors on its surface to stop the signal.
Negative regulation can occur at the receptor level through internalization, degradation, or dephosphorylation of CSF1R. Heterotrimeric Gi2 proteins have been shown to regulate CSF1-induced proliferation, suggesting a feedback mechanism that dampens receptor-proximal signaling. Additionally, microRNA-148b can suppress CSF1 signaling components, reducing downstream activation.
Intracellular inhibitory proteins
In simple terms: Inside the cell, specific proteins block the signal by interfering with signaling molecules.
Suppressors of cytokine signaling (SOCS) proteins are induced by cytokines and act as negative feedback inhibitors of JAK/STAT pathways, which are downstream of CSF1R. Sipa1 has been identified as a driver of maladaptive fibroblast-myeloid axis after myocardial infarction, potentially through modulation of M-CSF signaling.
MicroRNA-mediated suppression
In simple terms: Small RNA molecules reduce the production of proteins needed for the M-CSF signal.
MicroRNA-148b targets colony-stimulating factor-1 signaling, leading to decreased tumor-associated macrophage infiltration and reduced hepatocellular carcinoma metastasis. This exemplifies how microRNAs can act as negative regulators of the entire pathway.
Transcriptional and epigenetic control
In simple terms: The cell can turn off genes that promote M-CSF signaling or turn on genes that inhibit it.
M-CSF itself regulates transcription of target genes such as urokinase-type plasminogen activator, and negative regulation may involve transcriptional repression of CSF1 or CSF1R. Hypoxia-inducible factor-dependent signaling between breast cancer cells and mesenchymal stem cells promotes macrophage recruitment, indicating that microenvironmental cues can override negative regulation.
Key Genes Involved in GO:1902227 negative regulation of macrophage colony-stimulating factor signaling pathway
The following genes and proteins are experimentally implicated in the negative regulation of M-CSF signaling or in the pathway being regulated.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CSF1 | Ligand for CSF1R; activates M-CSF signaling | Target for negative regulation; overexpression models |
| CSF1R | Receptor tyrosine kinase; initiates signaling | Knockout and point-mutation studies |
| MIR148B | MicroRNA that suppresses CSF1 signaling | Negative regulator; KO/mimic studies |
| SOCS1 | Cytokine signaling suppressor | Negative feedback; KO models |
| SOCS3 | Cytokine signaling suppressor | Negative feedback; KO models |
| GNAI2 | Heterotrimeric Gi2 protein; regulates proliferation | Negative regulation of CSF1-induced proliferation |
| SIPA1 | Signal-induced proliferation-associated 1 | Drives maladaptive fibroblast-myeloid axis |
| HIF1A | Hypoxia-inducible factor 1-alpha | Promotes macrophage recruitment in breast cancer |
| PLAU | Urokinase-type plasminogen activator | Transcriptionally regulated by M-CSF |
| IL10 | Anti-inflammatory cytokine | Negatively regulated by GM-CSF; related pathway |
| CSF2 | Granulocyte-macrophage colony-stimulating factor | Related cytokine; negative regulation of IL-10 responses |
| JAK1 | Janus kinase 1; downstream of CSF1R | Target of SOCS-mediated inhibition |
| STAT3 | Signal transducer and activator of transcription 3 | Downstream effector; inhibited by SOCS |
| PIK3CA | Phosphatidylinositol 3-kinase catalytic subunit alpha | Downstream of CSF1R; potential negative regulation node |
| AKT1 | AKT serine/threonine kinase 1 | Survival signaling downstream of CSF1R |
| MAPK1 | Mitogen-activated protein kinase 1 | Proliferation signaling downstream of CSF1R |
| NFKB1 | Nuclear factor kappa B subunit 1 | Inflammatory signaling; modulated by M-CSF |
| TGFB1 | Transforming growth factor beta 1 | Microenvironmental regulator of macrophage recruitment |
How Is negative regulation of macrophage colony-stimulating factor signaling pathway Regulated?
The negative regulation of M-CSF signaling is itself controlled by multiple feedback loops. Cytokine-inducible SOCS proteins are rapidly upregulated upon CSF1R activation and subsequently inhibit JAK/STAT signaling, providing a classic negative feedback mechanism. MicroRNAs such as miR-148b are transcriptionally regulated and can be induced under specific conditions to suppress CSF1 signaling. Additionally, heterotrimeric Gi2 proteins modulate CSF1-induced proliferation, suggesting that G-protein-coupled signaling intersects with the negative regulation of this pathway. Hypoxia-inducible factors can promote macrophage recruitment by enhancing M-CSF signaling, thereby counteracting negative regulation in the tumor microenvironment.
negative regulation of macrophage colony-stimulating factor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MIR148B | Hepatocellular carcinoma metastasis | Knockout and overexpression in HCC cell lines |
| SIPA1 | Myocardial infarction | Knockout mouse models |
| HIF1A | Breast cancer macrophage recruitment | Knockdown in triple-negative breast cancer cells |
| SOCS1/SOCS3 | Chronic inflammation | Knockout mice and macrophage-specific deletion |
| CSF1R | Monocyte differentiation and metabolism | Point-mutation and knock-in models |
Hepatocellular carcinoma
MicroRNA-148b-mediated negative regulation of CSF1 signaling suppresses tumor-associated macrophage infiltration and inhibits hepatocellular carcinoma metastasis. Loss of this negative regulation leads to increased macrophage recruitment and tumor progression.
Myocardial infarction
Sipa1 drives a maladaptive fibroblast-myeloid axis after myocardial infarction, potentially by modulating M-CSF signaling. Negative regulation of this axis may be cardioprotective.
Breast cancer
Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment, which may involve overcoming negative regulation of M-CSF signaling.
Chronic inflammation
SOCS proteins negatively regulate cytokine signaling, including M-CSF pathways, and their dysfunction is associated with chronic inflammatory diseases. Granulocyte-macrophage colony-stimulating factor negatively regulates early IL-10-mediated responses, highlighting cross-talk between colony-stimulating factors and anti-inflammatory circuits.
From negative regulation of macrophage colony-stimulating factor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate M-CSF signaling? | CRISPR knockout in macrophage cell lines |
| Does a point mutation in CSF1R alter negative regulation? | Point-mutation knock-in via CRISPR |
| Can overexpression of miR-148b suppress M-CSF signaling? | Overexpression lentiviral models |
| What is the role of Gi2 in CSF1-induced proliferation? | Knockout of GNAI2 in hematopoietic cells |
| How does Sipa1 modulate fibroblast-myeloid axis? | Knockout mouse models of myocardial infarction |
| Does SOCS1 feedback inhibit M-CSF signaling? | Knockout and tagged knock-in of SOCS1 |
How to Study the negative regulation of macrophage colony-stimulating factor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Loss-of-function phenotypes | Identify negative regulators of M-CSF signaling |
| RNA-seq | Transcriptional changes | Discover microRNAs and inhibitory genes |
| Phosphoproteomics | Phosphorylation events | Map signaling nodes and phosphatases |
| Flow cytometry | Surface marker expression | Assess macrophage differentiation |
| Immunoblotting | Protein levels and phosphorylation | Validate CSF1R and downstream signaling |
| Luciferase reporter assay | Transcriptional activity | Measure promoter regulation by M-CSF |
| MicroRNA mimic/inhibitor | MicroRNA function | Test miR-148b-mediated suppression |
| In vivo mouse models | Tissue macrophage infiltration | Study myocardial infarction and cancer [1,2] |
CRISPR knockout screening
Genome-wide CRISPR knockout screens can identify negative regulators of M-CSF signaling by selecting for cells that survive or proliferate in the presence of M-CSF. This approach has been used to uncover genes involved in monocyte differentiation and metabolism.
RNA sequencing and transcriptomics
RNA-seq can reveal transcriptional changes in response to M-CSF and identify microRNAs or inhibitory proteins that are induced as part of negative feedback [3,7].
Proteomics and phosphoproteomics
Mass spectrometry-based phosphoproteomics can map the phosphorylation events downstream of CSF1R and identify phosphatases or inhibitory proteins that attenuate signaling.
Imaging and flow cytometry
Flow cytometry can measure macrophage surface markers and CSF1R internalization, while imaging can track receptor trafficking and macrophage recruitment in tissues [1,2].
How CRISPR Can Be Used to Study GO:1902227 negative regulation of macrophage colony-stimulating factor signaling pathway
Knockout
CRISPR knockout of candidate negative regulators such as SOCS1, SOCS3, or MIR148B can test whether loss of function enhances M-CSF signaling and macrophage activation [3,7]. Knockout of CSF1R itself abolishes signaling and serves as a positive control.
Point Mutation
Point mutations in CSF1R or downstream kinases can dissect specific phosphorylation sites required for negative regulation. For example, mutation of tyrosine residues in CSF1R can prevent recruitment of inhibitory proteins.
Knock-in
Knock-in of tagged versions of CSF1R or SOCS proteins allows tracking of protein localization and interactions during negative regulation. This can reveal dynamic trafficking of receptors.
Overexpression
Overexpression of microRNA-148b or SOCS proteins can suppress M-CSF signaling and reduce macrophage infiltration, providing gain-of-function evidence for negative regulation [3,7].
How EDITGENE Supports negative regulation of macrophage colony-stimulating factor signaling pathway Research
Researchers studying negative regulation of macrophage colony-stimulating factor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in attenuating M-CSF signaling. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models for such functional studies.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of macrophage colony-stimulating factor signaling pathway research.
Frequently Asked Questions About negative regulation of macrophage colony-stimulating factor signaling pathway
What is GO:1902227?
GO:1902227 is a Gene Ontology biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of macrophage colony-stimulating factor signaling pathway [1,4].
What genes are involved in negative regulation of M-CSF signaling?
Key genes include MIR148B, SOCS1, SOCS3, GNAI2, and SIPA1, which act at different levels to attenuate M-CSF signaling [2,3,4,7].
How does M-CSF signaling get turned off?
M-CSF signaling is turned off by receptor internalization, dephosphorylation, induction of SOCS proteins, and microRNA-mediated suppression of pathway components [3,4,7].
What diseases are linked to dysregulated M-CSF signaling?
Dysregulated M-CSF signaling is linked to hepatocellular carcinoma metastasis, myocardial infarction, breast cancer, and chronic inflammation [1,2,3,7].
What is the role of microRNA-148b in M-CSF signaling?
MicroRNA-148b negatively regulates CSF1 signaling, reducing tumor-associated macrophage infiltration and inhibiting hepatocellular carcinoma metastasis.
How can CRISPR be used to study negative regulation of M-CSF signaling?
CRISPR knockout, point mutation, knock-in, and overexpression models allow functional dissection of negative regulators such as SOCS proteins and microRNAs [3,5,7].
What is the relationship between CSF1R and M-CSF?
CSF1R is the receptor tyrosine kinase that binds M-CSF (CSF1) to initiate signaling; negative regulation often targets CSF1R activity or stability.
What are SOCS proteins and how do they regulate M-CSF signaling?
SOCS proteins are cytokine-inducible inhibitors of JAK/STAT signaling that provide negative feedback downstream of CSF1R.
Can overexpression of miR-148b suppress tumor growth?
Overexpression of miR-148b suppresses CSF1 signaling and reduces tumor-associated macrophage infiltration, inhibiting hepatocellular carcinoma metastasis in experimental models.
What experimental models are used to study GO:1902227?
Common models include CRISPR knockout macrophage cell lines, knockout mice, and overexpression systems for microRNAs or inhibitory proteins [2,3,5,7].
Conclusion
GO:1902227, negative regulation of macrophage colony-stimulating factor signaling pathway, is a critical biological process that controls the duration and intensity of M-CSF signaling. Its dysregulation contributes to cancer progression, cardiac remodeling, and chronic inflammation [1,2,3,7]. By leveraging CRISPR-based knockout, knock-in, and overexpression models, researchers can systematically dissect the molecular players involved and identify therapeutic targets. EDITGENE provides end-to-end services to accelerate this research.
References
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- 2. Ko S et al.. 2025. Sipa1 Drives a Maladaptive Fibroblast-Myeloid Axis After Myocardial Infarction.. Circ Res 137(4):533-547 PMID: 40567222
- 3. Ke M et al.. 2019. MicroRNA-148b-colony-stimulating factor-1 signaling-induced tumor-associated macrophage infiltration promotes hepatocellular carcinoma metastasis.. Biomed Pharmacother 120:109523 PMID: 31655310
- 4. Corre I et al.. 1995. Regulation of colony-stimulating factor 1-induced proliferation by heterotrimeric Gi2 proteins.. Blood 86(5):1776-83 PMID: 7655008
- 5. Gallerand A et al.. 2026. CSF1R regulates monocyte subset differentiation and intracellular metabolism.. Nat Commun 17(1) PMID: 42401537
- 6. Stacey KJ et al.. 1995. Regulation of urokinase-type plasminogen activator gene transcription by macrophage colony-stimulating factor.. Mol Cell Biol 15(6):3430-41 PMID: 7760840
- 7. Hanada T et al.. 2002. Regulation of cytokine signaling and inflammation.. Cytokine Growth Factor Rev 13(4-5):413-21 PMID: 12220554
- 8. Wilbers RH et al.. 2018. Granulocyte-macrophage colony-stimulating factor negatively regulates early IL-10-mediated responses.. Future Sci OA 4(4):FSO288 PMID: 29682323
