TLR2 and 4 signaling pathways are altered in macrophages from V30M TTR mice with down-regulated expression of chemokines.

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.