The inflammatory response to sciatic nerve injury in a familial amyloidotic polyneuropathy mouse model

• A FAP mouse model lays down TTR in response to peripheral nerve trauma.
• Transgenic TTR is dynamically regulated in response to an inflammatory insult.
• FAP mice had lower pro-inflammatory response to nerve injury as compared with WT.
• Delayed nerve regeneration after injury in FAP transgenic mice

Inflammation is a hallmark of several neurodegenerative disorders including familial amyloidotic polyneuropathy (FAP). FAP is associated with extracellular deposition of mutant transthyretin (TTR), leading to degeneration of cells and tissues, particularly in the peripheral nervous system (PNS). With this work, our goal was to characterize the expression/deposition of TTR and the associated inflammatory immune response, induced by nerve injury, in WT mice and in a mouse model carrying the most common TTR mutation in FAP (V30M). Our results indicate that upon nerve injury TTR is significantly produced by Schwann cells and is dynamically regulated over time in V30M mice, accompanying a peak of inflammation. Strikingly, V30M TTR deposition in nerve tissue occurred, suggesting that inflammation contributes to TTR polymerization. In response to nerve injury, V30M mice display a downregulated innate immune response when compared to WT mice. More specifically, we saw decreased expression of cytokines and chemokines important for the recruitment of immune cells like macrophages and neutrophils, known to be important for the tissue regenerative process which was found impaired in V30M mice. In conclusion, with this work we were able to characterize the biology of TTR both in WT and V30M animals, upon nerve injury, and found that V30M TTR impairs the inflammatory response necessary for nerve regeneration. Taken together, our findings suggest that inflammation is an important target to be considered in therapeutic strategies for FAP.