MSR1 - macrophage scavenger receptor 1 |Elisa - Clia - Antibody - Protein

Background

Macrophage Scavenger Receptor 1 (MSR1), also known as CD204, is a multifunctional receptor primarily expressed on macrophages and other cells of the mononuclear phagocyte system. MSR1 is a critical player in the immune system, where it recognizes and binds to various ligands, including modified lipoproteins, pathogens, and apoptotic cells, thereby aiding in host defense, tissue homeostasis, and inflammation. MSR1 functions by clearing endogenous and exogenous substances from the bloodstream and tissues, including oxidized low-density lipoproteins (oxLDL), a process essential in preventing atherosclerosis and other inflammatory diseases. Due to its role in these processes, MSR1 has been studied extensively in the context of immune responses, pathogen recognition, and chronic inflammatory conditions, including cardiovascular diseases and cancer.

Protein Structure

MSR1 is a type II transmembrane glycoprotein encoded by the MSR1 gene on chromosome 8p22. The protein structure of MSR1 is complex, with distinct domains that enable its broad range of ligand-binding capabilities and interactions with other proteins. The structural components of MSR1 include:

Cytoplasmic Domain:

• The cytoplasmic tail of MSR1 contains regulatory motifs critical for receptor function and signal transduction. This domain facilitates interactions with intracellular signaling molecules that are essential for the receptor’s endocytic and phagocytic functions.

Transmembrane Domain:

• The transmembrane segment of MSR1 anchors the receptor in the plasma membrane, positioning it to interact with extracellular ligands. This hydrophobic domain is a single-pass segment and is crucial for stabilizing the receptor on the cell surface.

Extracellular Domain

The extracellular domain of MSR1 has a highly specialized, modular architecture that includes:

• Collagen-like Domain: This domain is vital for ligand binding and contributes to the receptor’s recognition of modified lipoproteins, apoptotic cells, and certain pathogens. The collagen-like region facilitates binding through a series of repetitive Gly-X-Y motifs, where X and Y are frequently proline and hydroxyproline.
• α-helical Coiled-coil Domain: The coiled-coil domain provides structural stability and may facilitate multimerization, allowing MSR1 to function as a homotrimer. Trimerization enhances its ability to bind and uptake a broad range of ligands, thus expanding its functionality in immune recognition and scavenging.

This distinct structural organization allows MSR1 to recognize a variety of ligands with low affinity but high avidity, meaning it can bind multiple ligands simultaneously, enhancing its role in innate immunity and homeostasis.

Classification and Subtypes

MSR1 belongs to the class A family of scavenger receptors, known for their role in binding and internalizing a diverse range of endogenous and exogenous molecules. Within the MSR1 family, alternative splicing results in the production of different isoforms with slightly varied functions:

MSR1 Isoform I:

• This is the full-length form of the receptor and is responsible for most of the known scavenging functions, including the binding and internalization of modified lipoproteins, apoptotic cells, and microbial components.

MSR1 Isoform II:

• Isoform II lacks a portion of the collagen-like domain, which can affect its ability to bind certain ligands. This isoform still retains endocytic function but may have reduced affinity for some ligands compared to Isoform I.

MSR1 Isoform III:

• This isoform lacks most of the extracellular domain, rendering it inactive in ligand binding. However, Isoform III may have a regulatory role by affecting receptor signaling or trafficking on the cell surface.

Function and Biological Significance

MSR1 is involved in several critical functions within the immune system:

Pathogen Recognition and Immune Defense:

• MSR1 recognizes and binds bacterial components, such as lipopolysaccharides (LPS) and lipoteichoic acids, as well as fungal and viral particles, enabling phagocytic clearance of pathogens by macrophages. It thus plays a role in innate immunity by detecting and eliminating infectious agents.

Atherosclerosis Prevention:

• MSR1 is essential for clearing modified lipoproteins, such as oxLDL, from the bloodstream. This process prevents the accumulation of lipoproteins in vessel walls, which can lead to the formation of atherosclerotic plaques. Through its scavenging function, MSR1 helps reduce the risk of cardiovascular diseases by removing oxidized lipids that contribute to inflammation and plaque development.

Apoptotic Cell Clearance:

• MSR1 can bind to apoptotic cells and cellular debris, facilitating their clearance by macrophages. This function is essential for maintaining tissue homeostasis and preventing chronic inflammation that may result from the accumulation of dead or dying cells.

Tumor Biology and Cancer:

• MSR1’s role in recognizing damaged or altered cells extends to cancer, where it may influence tumor-associated macrophages (TAMs). In tumors, MSR1 expression on TAMs has been linked to both pro-tumor and anti-tumor activities, depending on the microenvironment and type of cancer. In some cases, MSR1-positive TAMs can suppress anti-tumor immunity, promoting tumor growth and metastasis. Conversely, MSR1 can aid in recognizing and clearing necrotic cells within the tumor, which may have anti-tumor effects.

Modulation of Inflammatory Response:

• Through its role in clearing inflammatory ligands such as oxidized lipids and dead cells, MSR1 plays a crucial part in resolving inflammation. This function is particularly significant in chronic inflammatory conditions, where impaired scavenging can contribute to prolonged immune activation.

Clinical Issues

MSR1 has been implicated in several diseases due to its role in immune responses and clearance of potentially harmful ligands:

Cardiovascular Diseases:

• Given its role in clearing oxLDL, MSR1 is essential in preventing atherosclerosis. Dysfunctional MSR1 or inadequate expression may lead to excessive lipid accumulation in the arterial walls, promoting plaque formation and increasing the risk of cardiovascular disease.

Cancer:

• MSR1 expression is prominent in TAMs, which have complex roles in cancer. In many cancers, TAMs promote tumor progression by creating an immunosuppressive environment. Thus, targeting MSR1 to alter TAM function could present a therapeutic strategy for enhancing anti-tumor immunity.

Chronic Inflammatory Diseases:

• In conditions such as rheumatoid arthritis and chronic obstructive pulmonary disease, dysregulation of MSR1 function can contribute to sustained inflammation. By affecting the clearance of inflammatory cells and mediators, altered MSR1 expression or activity can exacerbate chronic inflammatory states.

Infectious Diseases:

• MSR1 aids in immune defense by binding to various microbial components. Variations in MSR1 function may influence susceptibility to infections, including bacterial and viral infections, by impacting pathogen clearance efficiency.

Summary

MSR1 is a critical receptor in the immune system, functioning primarily on macrophages to bind and clear a range of ligands, including pathogens, modified lipoproteins, and apoptotic cells. Structurally, MSR1 consists of a cytoplasmic domain, transmembrane region, and extracellular domains with a collagen-like structure essential for binding diverse ligands. Isoforms of MSR1 provide functional diversity, with Isoform I being the most active in scavenging, while Isoforms II and III have altered or minimal ligand-binding capabilities. Functionally, MSR1 contributes to pathogen recognition, lipid homeostasis, and immune regulation, playing a significant role in atherosclerosis prevention, cancer biology, and inflammatory disease modulation.

Clinically, MSR1 is implicated in various conditions. Its dysfunction or dysregulation can contribute to cardiovascular diseases due to impaired clearance of oxidized lipids, exacerbate chronic inflammation in conditions like rheumatoid arthritis, and affect the immune response in cancer by modulating TAM activity. MSR1 remains a focus of research due to its role in innate immunity, tissue homeostasis, and potential as a therapeutic target in diseases where inflammation, immune dysregulation, or lipid accumulation play a pivotal role.