Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system

Abstract

BackgroundIncreasing evidence supports a key role for inflammation in the neurodegenerative process of familial amyloidotic polyneuropathy (FAP). While there seems to be an overactivation of the neuronal interleukin-1 signaling pathway, the immune response is apparently compromised in FAP. Accordingly, little immune cell infiltration is observed around pre-fibrillar or fibrillar amyloid deposits, with the underlying mechanism for this phenomenon remaining poorly understood. Cathepsin E (CtsE) is an important intermediate for antigen presentation and chemotaxis, but its role in the pathogenesis of FAP disease remains unknown.MethodsIn this study, we used both mouse primary macrophages and in vivo studies based on transgenic models of FAP and human samples to characterize CtsE expression in different physiological systems.ResultsWe show that CtsE is critically decreased in bone marrow-derived macrophages from a FAP mouse model, possibly contributing for cell function impairment. Compromised levels of CtsE were also found in injured nerves of transgenic mice and, most importantly, in naïve peripheral nerves, sensory ganglia, murine stomach, and sural nerve biopsies derived from FAP patients. Expression of CtsE in tissues was associated with transthyretin (TTR) deposition and differentially regulated accordingly with the physiological system under study. Preventing deposition with a TTR small interfering RNA rescued CtsE in the peripheral nervous system (PNS). In contrast, the expression of CtsE increased in splenic cells (mainly monocytes) or peritoneal macrophages, indicating a differential macrophage phenotype.ConclusionAltogether, our data highlights the potential of CtsE as a novel FAP biomarker and a possible modulator for innate immune cell chemotaxis to the disease most affected tissues—the peripheral nerve and the gastrointestinal tract.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0891-9) contains supplementary material, which is available to authorized users.

In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis

“…Mice were kept in a controlled temperature room and maintained under a 12 h light/dark period. Transgenic mice carrying human TTR V30M (HM30) were bred as described before [51]. Both younger (12-13 months; n = 12) and older (16-21 months; n = 7) HM30 mice were subcutaneously (s.c) injected once a week with 5 mg ASO/kg body weight following previous protocols [48].…”

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…Abnormal expression and/or activity of CTSs have been associated with a variety of human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and many others ( Table 1). [37,45] [ 46,47] [48] Figure 1. Cellular localization of cathepsins (CTSs).…”

Impaired in vitro growth response of plasma-treated cardiomyocytes predicts poor outcome in patients with transthyretin amyloidosis

“…In contrast to other so-far established biomarkers quantified in absolute numbers for their concentration, the HI represents a functional novel innovative approach integrating the significance of multiple agents in the plasma of patients into one read-out parameter. The exact underlying mechanism for altered hypertrophic response in our assay remains cryptic, while it can be speculated that the amyloid itself, catecholamines, inflammatory markers, antibodies, effects by cellular immunity or other not yet identified mediators will affect the final read-out [4,5,[34][35][36][37].…”