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Impaired function of Fanconi anemia type C-deficient macrophages
Ying Liu1, Kimberly Ballman, Deqiang Li
1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Abstract:
FA is a genetic disorder characterized by BM failure, developmental defects, and cancer predisposition. Previous studies suggest that FA patients exhibit alterations in immunologic function. However, it is unclear whether the defects are immune cell-autonomous or secondary to leukopenia from evolving BM failure. Given the central role that macrophages have in the innate immune response, inflammation resolution, and antigen presentation for acquired immunity, we examined whether macrophages from Fancc-/- mice exhibit impaired function. Peritoneal inflammation induced by LPS or sodium periodate resulted in reduced monocyte/macrophage recruitment in Fancc-/- mice compared with WT controls. Fancc-/- mice also had decreased inflammatory monocytes mobilized into the peripheral blood after LPS treatment compared with controls. Furthermore, Fancc-/- peritoneal macrophages displayed cell-autonomous defects in function, including impaired adhesion to FN or endothelial cells, reduced chemoattractant-mediated migration, and decreased phagocytosis. Moreover, dysregulated F-actin rearrangement was detected in Fancc-/- macrophages after adhesion to FN, which was consistent with an observed reduction in RhoA-GTP levels. Importantly, these data suggest that impaired cytoskeletal rearrangements in Fancc-/- macrophages may be the common mechanism responsible for cell-autonomous defects detected in vitro, as well as altered monocyte/macrophage trafficking in vivo.
Insights
Fanconi anemia (FA) macrophages show cell-autonomous defects, impacting immune responses. Impaired cytoskeletal rearrangement is a key mechanism affecting monocyte function and trafficking in FA.
Area of Science:
- Immunology
- Genetics
- Cell Biology
Background:
- Fanconi anemia (FA) is a genetic disorder causing bone marrow (BM) failure, developmental issues, and cancer risk.
- FA patients show immune system alterations, but it's unclear if these are intrinsic to immune cells or due to BM failure.
- Macrophages are crucial for innate immunity, inflammation control, and antigen presentation.
Purpose of the Study:
- To investigate if macrophages from Fancc-/- mice (a model for FA) have impaired functions.
- To determine if observed immune defects in FA are cell-autonomous in macrophages.
Main Methods:
- Inducing peritoneal inflammation using LPS or sodium periodate in Fancc-/- and WT mice.
- Analyzing monocyte/macrophage recruitment and mobilization.
- Assessing Fancc-/- peritoneal macrophage functions in vitro: adhesion, migration, and phagocytosis.
- Examining F-actin rearrangement and RhoA-GTP levels in Fancc-/- macrophages.
Main Results:
- Fancc-/- mice exhibited reduced monocyte/macrophage recruitment during peritoneal inflammation.
- Fewer inflammatory monocytes were mobilized into peripheral blood in Fancc-/- mice post-LPS.
- Fancc-/- macrophages showed cell-autonomous defects: impaired adhesion, reduced migration, and decreased phagocytosis.
- Dysregulated F-actin rearrangement and reduced RhoA-GTP levels were observed in Fancc-/- macrophages.
Conclusions:
- Macrophages from Fancc-/- mice display intrinsic functional impairments.
- Altered cytoskeletal dynamics, specifically F-actin rearrangement and RhoA signaling, underlie these macrophage defects.
- These findings suggest impaired cytoskeletal function is a common mechanism for cell-autonomous macrophage defects and altered in vivo trafficking in FA.
