The Expression of Chemokines Is Downregulated in a Pre-Clinical Model of TTR V30M Amyloidosis.

João Moreira,Maria João Saraiva,Susete Costelha,Margarida Saraiva

doi:10.3389/fimmu.2021.650269

Abstract

Inflammation is a hallmark of several neurodegenerative disorders including hereditary amyloidogenic transthyretin amyloidosis (ATTRv). ATTRv is an autosomal dominant neurodegenerative disorder with extracellular deposition of mutant transthyretin (TTR) aggregates and fibrils, particularly in nerves and ganglia of the peripheral nervous system. Nerve biopsies from ATTRv patients show increased cytokine production, but interestingly no immune inflammatory cellular infiltrate is observed around TTR aggregates. Here we show that as compared to Wild Type (WT) animals, the expression of several chemokines is highly downregulated in the peripheral nervous system of a mouse model of the disease. Interestingly, we found that stimulation of mouse Schwann cells (SCs) with WT TTR results in the secretion of several chemokines, a process that is mediated by toll-like receptor 4 (TLR4). In contrast, the secretion of all tested chemokines is compromised upon stimulation of SCs with mutant TTR (V30M), suggesting that V30M TTR fails to activate TLR4 signaling. Altogether, our data shed light into a previously unappreciated mechanism linking TTR activation of SCs and possibly underlying the lack of inflammatory response observed in the peripheral nervous system of ATTRv patients.

Highlights

Amyloid disorders are a heterogeneous group of diseases that can either be focal or systemic
The expression of most chemokines was significantly downregulated in the sciatic nerve of HSF V30M TTR mice when compared to HSF Wild Type (WT) control at 6 months of age (Table 1), a finding that we validated by Real-time PCR (RT-PCR) (Figure 1A)
We showed an impairment in the production of several chemokines in the peripheral nervous system of a pre-clinical model of TTR V30M amyloidosis

Summary

Introduction

Amyloid disorders are a heterogeneous group of diseases that can either be focal or systemic. They are due to the extracellular deposition of insoluble misfolded proteins, disrupting normal tissue function [1]. Transthyretin (TTR) amyloidosis is the most common form of hereditary autosomic dominant systemic amyloidosis, in which TTR point mutations result in deposition of amyloidogenic species in different tissues [2]. This disease has been designated as ATTRv [3]. The expression of TTR was recently reported in Schwann cells (SCs) of the sciatic nerve [7], but this protein is mainly synthesized in the liver and choroid plexus of the brain being secreted into the blood stream and cerebrospinal fluid, respectively [8, 9]

Methods

Results

Conclusion