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Efferocytosis is impaired in Gaucher macrophages
Elma Aflaki1, Daniel K Borger1, Richard J Grey1
1Section of Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD, USA.
Abstract:
Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylceramide-laden macrophages resulting from impaired digestion of aged erythrocytes or apoptotic leukocytes. Studies of macrophages from patients with type 1 Gaucher disease with genotypes N370S/N370S, N370S/L444P or N370S/c.84dupG revealed that Gaucher macrophages have impaired efferocytosis resulting from reduced levels of p67phox and Rab7. The decreased Rab7 expression leads to impaired fusion of phagosomes with lysosomes. Moreover, there is defective translocation of p67phox to phagosomes, resulting in reduced intracellular production of reactive oxygen species. These factors contribute to defective deposition and clearance of apoptotic cells in phagolysosomes, which may have an impact on the inflammatory response and contribute to the organomegaly and inflammation seen in patients with Gaucher disease.
Insights
Gaucher disease macrophages show impaired efferocytosis due to reduced p67phox and Rab7 levels. This impacts the clearance of apoptotic cells, potentially contributing to Gaucher disease
Area of Science:
- Cell Biology
- Lysosomal Storage Disorders
- Immunology
Background:
- Gaucher disease is an inherited lysosomal storage disorder caused by glucocerebrosidase deficiency.
- It leads to the accumulation of glucosylceramide in macrophages, particularly affecting aged erythrocytes and apoptotic leukocytes.
- This accumulation contributes to the characteristic organomegaly and inflammation observed in patients.
Purpose of the Study:
- To investigate the cellular mechanisms underlying impaired efferocytosis in Gaucher disease macrophages.
- To identify key molecular factors contributing to defective phagosome-lysosome fusion and apoptotic cell clearance.
Main Methods:
- Analysis of macrophages from Gaucher disease patients with specific genotypes (N370S/N370S, N370S/L444P, N370S/c.84dupG).
- Assessment of efferocytosis, p67phox and Rab7 protein levels, phagosome-lysosome fusion, and reactive oxygen species production.
Main Results:
- Gaucher macrophages exhibit significantly impaired efferocytosis.
- Reduced levels of p67phox and Rab7 were observed in Gaucher macrophages.
- Defective translocation of p67phox to phagosomes and impaired phagosome-lysosome fusion were identified.
- Reduced intracellular reactive oxygen species production was noted.
Conclusions:
- Impaired efferocytosis in Gaucher disease is linked to reduced p67phox and Rab7.
- Defective phagosome-lysosome fusion and reduced reactive oxygen species contribute to impaired apoptotic cell clearance.
- These cellular defects may play a role in the inflammatory responses and organomegaly seen in Gaucher disease.
