LAUSR

Hereditary transthyretin amyloidosis (ATTRv) is a fatal neurodegenerative disorder, firstly identified in Portugal. The most common 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 transthyretin (TTR), particularly in the nerves and ganglia of the peripheral nervous system. 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 downregulation in the expression of several chemokines by bone marrow derived macrophages (BMDM) generated from V30M TTR mice upon stimulation with TLR4 and TLR2 agonists. The phosphorylation of the MAP kinase p38, important for TLR4 and TLR2 signaling pathways, was also downregulated in V30M macrophages, as compared to wild-type ones.This 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.