Abstract
The relationship between familial amyloid polyneuropathy (FAP), which is caused by mutated transthyretin (TTR), and inflammation has only recently been noted. To determine whether inflammation is present in FAP carriers and patients, serum interleukin (IL)−6 concentration in 57 healthy donors (HD), 21 FAP carriers, and 66 FAP patients was examined, with the relationship between IL-6 and TTR assessed in each group by multiple regression analysis and structural equation models (SEM). Compared with HD, IL-6 concentration was elevated in FAP carriers (p = 0.001, 95% CI 0.398–1.571) and patients (p = 0.002, 95% CI 0.362–1.521). Further, SEM indicated a positive relationship between IL-6 and TTR in FAP carriers (p = 0.010, 95% CI 0.019–0.140), but not in HD and FAP patients. In addition, we determined whether TTR induces production of pro-inflammatory cytokines ex vivo. HD-derived CD14 + monocytes and induced pluripotent stem cell-derived myeloid lineage cells from a HD and FAP patient dose-dependently produced IL-6 under mutated and aggregated TTR conditions, compared with wild-type TTR. In conclusion, FAP carriers and patients are in an inflammatory state, with the presence of mutated TTR being a trigger of inflammation, especially in FAP carriers.
Highlights
Familial amyloid polyneuropathy (FAP) is a rare neurodegenerative disease showing autosomal dominant inheritance, which is caused by deposition of mutated transthyretin (TTR)-derived amyloid fibrils in several organs
We show that familial amyloid polyneuropathy (FAP) carriers and patients are in an inflammatory state, and in particular, FAP carrier-derived TTR positively affects IL-6 concentration
To determine the presence of inflammation, serum IL-6 and high-sensitivity C-reactive protein concentration were cross-sectionally analysed in healthy donors (HD) (n = 57), as well as FAP carriers (n = 21) and patients (n = 66) (Supplementary Table S1)
Summary
Familial amyloid polyneuropathy (FAP) is a rare neurodegenerative disease showing autosomal dominant inheritance, which is caused by deposition of mutated transthyretin (TTR)-derived amyloid fibrils in several organs. In a FAP mouse model, administration of an interleukin (IL)−1 antagonist inhibited TTR deposition at the sciatic nerve[5], while V122I mutated TTR affected expression of interleukin-6 (IL-6) in chondrocytes[6]. These results suggest that mutated TTR may affect pro-inflammatory cytokines. We show that FAP carriers and patients are in an inflammatory state, and in particular, FAP carrier-derived TTR positively affects IL-6 concentration. We confirmed this phenomenon using an ex vitro assay
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