CSF1R - colony stimulating factor 1 receptor | Elisa - Clia - Antibody - Protein

Background

The Colony Stimulating Factor 1 Receptor (CSF1R), also known as macrophage colony-stimulating factor receptor or CD115, is a cell surface receptor that primarily regulates the survival, proliferation, and differentiation of monocytes, macrophages, and osteoclasts. CSF1R is a transmembrane protein belonging to the receptor tyrosine kinase (RTK) family and is activated by binding to its primary ligand, colony-stimulating factor 1 (CSF1), as well as the alternative ligand interleukin-34 (IL-34). This receptor is essential for various immune functions and bone metabolism, primarily because of its role in maintaining and activating macrophage populations.

The CSF1R gene is located on chromosome 5 (5q32) and encodes a protein that is essential in regulating macrophage differentiation, survival, and function. CSF1R signaling influences immune response, inflammation, tissue homeostasis, and bone remodeling. Dysregulation of CSF1R or its signaling pathways has been associated with pathological conditions such as inflammatory diseases, cancer, and neurodegenerative disorders. Furthermore, mutations in CSF1R have been implicated in a group of disorders characterized by leukoencephalopathy and early-onset neurodegeneration.

Protein Structure

CSF1R is a single-pass type I transmembrane glycoprotein comprising approximately 972 amino acids. The protein can be divided into several domains, each contributing specific functions and facilitating ligand binding, receptor dimerization, and signal transduction.

Extracellular Domain:

• The extracellular domain contains five immunoglobulin-like (Ig-like) domains, which are crucial for ligand binding and receptor dimerization. These Ig-like domains provide structural support for interaction with CSF1 and IL-34.
• The first three Ig-like domains are responsible for the initial high-affinity ligand binding, while the remaining two play roles in stabilizing the receptor-ligand complex and facilitating receptor dimerization. Dimerization is required for receptor activation and downstream signaling.
• The extracellular domain also contains several N-linked glycosylation sites that enhance receptor stability and cell surface expression.

Transmembrane Domain:

• The transmembrane domain consists of a 23-amino acid hydrophobic segment that anchors CSF1R within the plasma membrane. This domain stabilizes the receptor within the lipid bilayer and serves as a structural anchor between the extracellular ligand-binding and intracellular signaling domains.

Intracellular (Cytoplasmic) Domain:

• The cytoplasmic domain of CSF1R contains the tyrosine kinase domain and is responsible for initiating downstream signaling cascades upon receptor activation. This domain contains several conserved tyrosine residues that, when phosphorylated, serve as docking sites for adaptor proteins.
• The tyrosine kinase domain functions by autophosphorylating tyrosine residues, leading to the recruitment and activation of downstream signaling proteins such as SRC homology 2 (SH2) domain-containing proteins.
• Key signaling pathways activated by CSF1R include PI3K-AKT, MAPK/ERK, and JAK-STAT pathways, which regulate cell survival, proliferation, migration, and differentiation.

Glycosylation Sites:

• Multiple N-linked glycosylation sites are present on the extracellular domain, which aid in the proper folding, stability, and receptor-ligand interactions of CSF1R.

Classification and Subtypes

CSF1R is classified as a class III receptor tyrosine kinase (RTK), specifically part of the platelet-derived growth factor receptor (PDGFR) family. CSF1R shares structural and functional similarities with other members of this family, including c-KIT and FLT3.

While there are no subtypes of CSF1R itself, it binds to two ligands, CSF1 and IL-34, which elicit both overlapping and unique biological functions. CSF1R-ligand interactions are crucial for the receptor’s diverse functions in different tissues and cell types.

Function and Biological Significance

CSF1R functions as a regulator of macrophage and osteoclast biology. By binding to CSF1 and IL-34, CSF1R activates several intracellular signaling pathways, impacting various physiological and pathological processes:

Macrophage Differentiation and Maintenance:

• CSF1R signaling is fundamental for macrophage lineage commitment, differentiation, survival, and maintenance. CSF1 promotes the proliferation of monocyte progenitors in the bone marrow and their differentiation into macrophages in peripheral tissues.
• This receptor is critical for the regulation of tissue-resident macrophages in multiple organs, including the liver, lung, and brain, where it helps sustain immune surveillance, tissue remodeling, and repair.

Osteoclast Differentiation and Bone Homeostasis:

• In osteoclast precursor cells, CSF1R is activated by CSF1 to promote osteoclast differentiation and function, leading to bone resorption. CSF1R is therefore vital for bone homeostasis and remodeling.
• Dysregulation of CSF1R signaling can result in bone disorders, either by excessive bone resorption or lack of adequate osteoclast activity.

Immune and Inflammatory Responses:

• CSF1R signaling modulates immune responses, particularly within the monocyte-macrophage lineage. It is implicated in the activation of macrophages, cytokine production, and the inflammatory response.
• Macrophages expressing CSF1R contribute to inflammation in conditions such as arthritis, atherosclerosis, and neuroinflammatory diseases.

Role in Cancer:

• CSF1R signaling is associated with the tumor microenvironment, where it plays a role in the recruitment of tumor-associated macrophages (TAMs). TAMs are known to promote tumor growth, angiogenesis, and metastasis by suppressing anti-tumor immune responses and enhancing the tumor’s ability to evade the immune system.
• CSF1R inhibition is a therapeutic target in cancer, aimed at reducing TAM recruitment and thereby slowing tumor progression.

Neuroprotection and Neurodegeneration:

• In the central nervous system, CSF1R expression in microglia supports neuroprotection and homeostasis under normal physiological conditions. However, mutations or dysregulation of CSF1R are linked to neurodegenerative disorders, including adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
• CSF1R signaling is necessary for microglial survival and maintenance, and disruption can lead to neurodegeneration due to microglial dysfunction.

Clinical Issues

Mutations and dysregulation of CSF1R are implicated in a variety of diseases:

Hematological Disorders:

• Although CSF1R is primarily associated with macrophages, mutations in CSF1R can also affect the hematopoietic system. Such mutations may contribute to altered immune cell differentiation, abnormal macrophage function, and an increased risk of inflammatory diseases.

Neurodegenerative Diseases:

• Mutations in CSF1R have been identified in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). ALSP is characterized by progressive cognitive decline, motor impairment, and neuroinflammation. CSF1R mutations disrupt normal microglial function, leading to neuronal degeneration and inflammation.
• Given the neuroprotective role of CSF1R in microglial cells, its dysfunction is a focal point for research into neuroinflammatory and neurodegenerative conditions.

Inflammatory Diseases:

• Aberrant CSF1R signaling has been associated with chronic inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and atherosclerosis. In these conditions, dysregulated CSF1R expression promotes macrophage-driven inflammation, contributing to tissue damage and disease progression.

Cancer:

• Overexpression of CSF1R or increased CSF1/IL-34 signaling is linked to the accumulation of TAMs in the tumor microenvironment. TAMs contribute to tumor progression by promoting angiogenesis, invasion, and metastasis while suppressing anti-tumor immune responses.
• Inhibitors targeting CSF1R are being explored as cancer therapies to deplete TAMs or inhibit their function, thereby enhancing the effectiveness of immunotherapy and reducing tumor growth.

Summary

CSF1R is a receptor tyrosine kinase essential for regulating macrophage and osteoclast biology, as well as immune response, bone homeostasis, and neuroprotection. Structurally, CSF1R consists of extracellular domains for ligand binding, a transmembrane domain, and a cytoplasmic domain with tyrosine kinase activity that activates downstream signaling. Binding of CSF1R with its ligands, CSF1 and IL-34, activates pathways like PI3K-AKT, MAPK/ERK, and JAK-STAT, facilitating macrophage differentiation, osteoclast function, and immune regulation.

Clinically, CSF1R dysregulation is associated with hematological disorders, neurodegenerative diseases such as ALSP, inflammatory conditions, and cancers. In cancer, CSF1R supports tumor progression by recruiting TAMs, making it a target for therapeutic interventions aimed at inhibiting TAM-mediated immunosuppression and enhancing anti-tumor immunity. CSF1R remains a critical focus in both basic and clinical research due to its wide-ranging physiological functions and its impact on human health.