MSR1 Human
Description
Molecular Structure and Isoforms
The MSR1 gene (ENSG00000038945) spans 11 exons on chromosome 8 and produces three splice variants through alternative splicing :
| Isoform | Key Features | Functional Status |
|---|---|---|
| SR-AI | Contains a collagen-like domain and cysteine-rich C-terminus; mediates ligand internalization | Functional |
| SR-AII | Lacks the cysteine-rich C-terminus; retains ligand-binding capability | Functional |
| SR-AIII | Truncated variant trapped in the endoplasmic reticulum | Dominant-negative regulator |
SR-AI and SR-AII form homo-trimers with six structural domains, including a collagen-like ligand-binding region enriched with lysine clusters for polyanionic ligand interactions .
Ligand Specificity and Binding
MSR1 binds diverse endogenous and exogenous ligands via its collagen-like domain :
| Ligand Type | Examples | Pathophysiological Role |
|---|---|---|
| Modified lipoproteins | Acetylated LDL, Oxidized LDL | Foam cell formation in atherosclerosis |
| Pathogen-associated | Bacterial lipopolysaccharides, viral particles | Host defense against infections |
| Cellular debris | Apoptotic cells, amyloid-β fibrils | Alzheimer’s disease progression |
| Inorganic particles | Silica, asbestos | Lung injury and fibrosis |
MSR1’s ligand promiscuity enables roles in both homeostatic clearance and disease exacerbation .
Expression and Regulation
MSR1 is predominantly expressed in macrophages but also detected in dendritic cells, vascular smooth muscle cells, and lung epithelial cells . Key regulatory mechanisms include:
-
Transcriptional control: LPS upregulates MSR1 via AP-1 and STAT2, while TNF-α and IFN-γ suppress it .
-
Epigenetic modulation: miR-155 suppresses MSR1 in macrophages, whereas miR-204 enhances its expression in atherosclerosis .
-
Genetic variants: The SNP rs41505344 alters transcription factor binding (MITF, MAF) upstream of MSR1, influencing disease susceptibility .
Cancer
In tumor-associated macrophages (TAMs), MSR1 promotes JNK-mediated inflammation, polarizing macrophages toward a pro-tumorigenic M2 phenotype. Elevated MSR1 correlates with poor prognosis in ovarian and lung cancers .
Neurodegeneration
MSR1 binds amyloid-β in Alzheimer’s disease, contributing to plaque formation but also aiding clearance in microglia, highlighting dual roles .
Infectious Diseases
MSR1 enhances antiviral responses (e.g., adenovirus, cytomegalovirus) but exacerbates hepatitis C and herpes simplex infections by modulating TLR3/9 signaling .
Signaling Pathways
Despite lacking intrinsic signaling domains, MSR1 triggers inflammation through:
-
K63-linked polyubiquitination: Recruits TAK1/MKK7/JNK complex, inducing TNF-α and IL-6 in macrophages .
-
Crosstalk with TLRs: Synergizes with TLR3/9 to activate IRF3 and NF-κB during viral sensing .
Therapeutic Targeting
-
Antibody blockade: Anti-MSR1 antibodies reduce cytokine production in preclinical models of atherosclerosis and cancer .
-
Gene silencing: siRNA targeting MSR1 inhibits foam cell formation and tumor progression .
Clinical and Research Implications
| Biomarker Potential | Therapeutic Target Areas | Challenges |
|---|---|---|
| Prognostic marker in COPD, asthma, and cancer | Atherosclerosis, NASH, bone metastasis | Context-dependent roles complicate drug design |
Product Specs
Q&A
What is MSR1 and what are its primary functions in humans?
MSR1 is a pattern recognition receptor primarily expressed on myeloid cells that recognizes both "self" and "non-self" ligands. It plays crucial roles in host defense against microbial infections and maintenance of immune homeostasis . MSR1 functions extend beyond simple phagocytosis, as its immunomodulatory activities can be uncoupled from its endocytic/phagocytic functions . Methodologically, researchers can investigate MSR1 function through receptor blocking experiments using inhibitors like fucoidan, which has shown efficacy in suppressing MSR1-mediated inflammation in experimental models .
Where is MSR1 expressed in human tissues and how is this best detected?
MSR1 shows predominant expression in macrophages across various tissues, with single nuclear RNA sequencing confirming macrophage-specific expression in human adipose tissue . It is also present on circulating and bone marrow neutrophils, where it can be upregulated in response to toll-like receptor 2 stimulation .
For detection methods:
-
Single nuclear RNA sequencing provides cellular resolution of MSR1 expression
-
Flow cytometry can quantify MSR1 surface expression on specific immune cell populations
-
Immunohistochemistry identifies tissue localization patterns
-
RT-qPCR measures transcript levels in bulk tissue samples
How does MSR1 expression differ between healthy individuals and those with metabolic disorders?
Increased MSR1 expression has been observed in visceral adipose tissue (VAT) of obese diabetic individuals compared to non-diabetic subjects . This upregulation appears to be macrophage-specific, as confirmed by single nuclear RNA sequencing of human adipose tissue . While MSR1 serves as a biomarker of diabetes status in human adipose tissue, experimental evidence from mouse models suggests it may not be required for obesity-associated insulin resistance or adipose tissue macrophage (ATM) accumulation .
What is the relationship between MSR1 and inflammatory liver conditions in humans?
MSR1 expression is strongly upregulated in the livers of patients with fulminant hepatitis (FH) . Mechanistic studies in mouse models reveal that Msr1 modulates the development of experimental FH through enhancing activation of the complement C5a/C5aR pathway . When testing the contribution of MSR1 to liver inflammation, researchers should consider:
-
Evaluating both expression levels and functional activity of MSR1
-
Measuring downstream inflammatory mediators including C5a
-
Assessing disease-specific outcomes like tissue damage and serum alanine aminotransferase
-
Considering potential therapeutic interventions targeting MSR1 function
What role does MSR1 play in autoimmune pathology?
MSR1 participates in the maintenance of immunological tolerance, with its dysfunction potentially contributing to autoimmune conditions . In experimental arthritis models, MSR1 regulates autoantigen concentration, with its absence leading to elevated serum levels of autoantigens . This finding reveals a previously unappreciated mechanism by which scavenger receptors may influence autoimmunity - through regulating the concentration and presentation of soluble autoantigens to the adaptive immune system .
What cellular assays best measure MSR1-mediated antigen uptake?
To quantify MSR1-mediated uptake of antigens such as glucose-6-phosphate isomerase (GPI), researchers should consider:
-
Flow cytometry-based internalization assays using fluorescently-labeled antigens
-
Competitive inhibition studies with known MSR1 ligands
-
Microscopy-based colocalization analysis with endosomal/lysosomal markers
-
Comparative assays between MSR1-sufficient and MSR1-deficient cells
Macrophages lacking MSR1 have been shown to be inefficient at taking up specific autoantigens, resulting in elevated serum concentrations of these molecules .
How can researchers evaluate the specific contribution of MSR1 to immune regulation?
To isolate MSR1-specific effects from other pattern recognition receptors:
-
Generate cell lines with MSR1 knockout or knockdown
-
Use MSR1-specific blocking antibodies in functional assays
-
Compare wild-type, heterozygous, and homozygous knockout models to detect gene dose effects
-
Perform bone marrow transplantation experiments between MSR1-sufficient and deficient animals
For example, arthritis developed normally when bone marrow from MSR1-deficient K/BxN mice was transplanted into hosts whose macrophages expressed MSR1, highlighting the importance of cell-specific MSR1 function .
How do contradictory findings about MSR1 in metabolic disease reconcile?
Contradictory reports about MSR1's role in obesity and glucose intolerance may be explained by several methodological factors:
What are key considerations for developing MSR1-targeted therapeutics?
When exploring MSR1 as a therapeutic target for conditions like fulminant hepatitis:
-
Consider targeting specific MSR1-ligand interactions rather than complete receptor inhibition
-
Evaluate both direct and indirect effects on complement activation
-
Monitor potential off-target effects on beneficial MSR1 functions like apoptotic cell clearance
-
Assess effects across different tissue macrophage populations
Studies suggest that drugs inhibiting MSR1 function could benefit patients with fulminant hepatitis, as demonstrated by the suppression of FH progression in mice treated with the MSR1 inhibitor fucoidan .
How should researchers address functional heterogeneity of MSR1 across different tissue environments?
MSR1 function varies considerably between tissue-resident macrophage populations. Research approaches should:
-
Compare MSR1+ macrophages isolated from different tissues within the same individual
-
Analyze the tissue-specific transcriptional program of MSR1+ cells using single-cell RNA sequencing
-
Identify tissue-specific MSR1 ligands using proteomics approaches
-
Evaluate the impact of the tissue microenvironment on MSR1 expression and function
For instance, the function of MSR1 in adipose tissue macrophages during obesity may differ significantly from its role in liver Kupffer cells during hepatitis .
What methodological approaches best evaluate MSR1 function in human samples?
When investigating MSR1 in human samples:
-
Isolate CD204+ myeloid cells from patient tissues for functional studies
-
Perform comparative transcriptomics between MSR1-high and MSR1-low patient subgroups
-
Develop in vitro systems using patient-derived cells to model disease-specific MSR1 functions
-
Measure soluble markers of MSR1 activity in patient biofluids
For example, in studies of metabolic disease, researchers might compare MSR1 expression and function in adipose tissue macrophages isolated from lean, obese non-diabetic, and obese diabetic individuals .
How can MSR1 genetic variants inform human disease mechanisms?
Analysis of MSR1 genetic variants requires:
-
Systematic assessment of variant effects on receptor expression, structure, and ligand binding
-
Correlation of variant prevalence with disease risk across populations
-
Development of cell models expressing specific variants to test functional consequences
-
Integration of genetic data with clinical outcomes to identify potential predictive biomarkers
MSR1 polymorphisms may influence disease susceptibility by altering the receptor's ability to clear autoantigens or modulate inflammatory responses .
Product Science Overview
MSR1 was first described in 1979 by Brown and Goldstein, who demonstrated its role in mediating the uptake and degradation of acetylated low-density lipoprotein (acetyl-LDL) . The receptor is involved in the phagocytosis of a wide range of ligands, including modified lipoproteins, apoptotic cells, and pathogens . This ability to bind and internalize diverse ligands makes MSR1 a key player in maintaining tissue homeostasis and immune response.
- Atherosclerosis: MSR1 is implicated in the development of atherosclerosis by mediating the uptake of modified lipoproteins, leading to the formation of foam cells and plaque development .
- Neurodegenerative Diseases: MSR1 is expressed by microglia in the central nervous system (CNS) and is involved in the uptake and clearance of amyloid-β, a key component in Alzheimer’s disease .
- Prion Diseases: Although MSR1 expression is upregulated in prion-infected brains, studies have shown that its deficiency does not significantly affect prion disease progression or prion clearance .
- Cancer: Emerging research suggests that MSR1 plays a role in tumor-associated macrophages, influencing tumor progression and metastasis .
