TLR2 and 4 signaling pathways are altered in macrophages from V30M TTR mice with down-regulated expression of
João Moreira1,2, Helena Martins1, Margarida Saraiva3
1Molecular Neurobiology Group, i3S - Instituto de Investigação e Inovação em Saúde, Department of Neurobiology and Neurologic Disorders, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal.
Abstract:
Hereditary amyloid transthyretin (ATTRv) amyloidosis is a fatal neurodegenerative disorder, first identified in Portugal. The most common transthyretin (TTR) mutation in ATTRv results from an exchange of a methionine for a valine at position 30 (V30M). ATTRv is characterized by the extracellular deposition of aggregates and fibrils of mutant forms of TTR, particularly in the nerves and ganglia of the peripheral nervous system (PNS). This phenotype is often accompanied by the lack of inflammatory infiltrates, despite the importance of macrophages in removal of TTR deposits in ATTRv patients. The mechanisms underlying this impairment of inflammatory responses in ATTRv patients are poorly understood. Here, we show a significant down-regulation in the expression of several chemokines by bone marrow-derived macrophages (BMDM) generated from V30M TTR mice upon stimulation with toll-like receptor 4 (TLR4) and TLR2 agonists. The phosphorylation of the MAP kinase p38, important for TLR4 and TLR2 signaling pathways, was also down-regulated in V30M macrophages, as compared with wild-type (WT) ones. The present study contributes with new insights to unravel the molecular mechanisms underlying the lack of inflammatory immune responses observed in ATTRv patients and may help in the development of new immune therapeutic strategies for the disease.
Insights
Hereditary transthyretin amyloidosis (ATTRv) involves impaired macrophage inflammatory responses. This study reveals reduced chemokine expression and p38 MAP kinase signaling in V30M TTR mice, offering insights into ATTRv immune dysfunction.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Genetics
Background:
- Hereditary transthyretin amyloidosis (ATTRv) is a fatal neurodegenerative disease caused by mutant transthyretin (TTR) protein aggregation.
- ATTRv pathology involves TTR deposits in the peripheral nervous system (PNS), often without significant inflammation.
- The mechanisms behind the impaired inflammatory response in ATTRv patients remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the suppressed inflammatory response in hereditary transthyretin amyloidosis.
- To examine the function of macrophages in the context of the V30M transthyretin mutation.
Main Methods:
- Generation of bone marrow-derived macrophages (BMDM) from V30M TTR mutant mice and wild-type (WT) controls.
- Stimulation of BMDM with toll-like receptor 4 (TLR4) and TLR2 agonists.
- Analysis of chemokine expression and p38 MAP kinase phosphorylation in stimulated macrophages.
Main Results:
- Macrophages derived from V30M TTR mice exhibited significantly down-regulated expression of several chemokines upon TLR4 and TLR2 stimulation.
- Phosphorylation of the p38 MAP kinase, crucial for TLR signaling, was also reduced in V30M macrophages compared to WT.
- These findings indicate an intrinsic impairment in the inflammatory signaling pathways of macrophages in the V30M TTR mouse model.
Conclusions:
- The study elucidates molecular mechanisms contributing to the lack of inflammatory responses in hereditary transthyretin amyloidosis.
- Down-regulation of chemokine expression and p38 signaling in macrophages is a key feature of the V30M TTR mutation.
- These insights may pave the way for developing novel immune-based therapeutic strategies for ATTRv.
