2. Academic Validation
  3. Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system

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

  • J Neuroinflammation. 2017 Jun 6;14(1):115. doi: 10.1186/s12974-017-0891-9.
Nádia Pereira Gonçalves 1 2 3,  João Moreira 1 2,  Diana Martins 1 2,  Paulo Vieira 4,  Laura Obici 5,  Giampaolo Merlini 5,  Margarida Saraiva 1 6,  Maria João Saraiva 7 8
Affiliations

Affiliations

  • 1 i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.
  • 2 Molecular Neurobiology Group, IBMC - Institute for Molecular and Cell Biology, University of Porto, 4150-180, Porto, Portugal.
  • 3 Present address: Department of Biomedicine/DANDRITE, Aarhus University, Ole Worms Alle 3, 1171, 8000, Aarhus C, Denmark.
  • 4 Unité du Développement des Lymphocytes, Département d'Immunologie, Institut Pasteur, Paris, 75724 CEDEX 15, France.
  • 5 Amyloidosis Research and Treatment Center, Department of Molecular Medicine, Fondazione Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, University of Pavia, Pavia, Italy.
  • 6 Immune Regulation Group, IBMC - Institute for Molecular and Cell Biology, University of Porto, 4150-180, Porto, Portugal.
  • 7 i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal. [email protected].
  • 8 Molecular Neurobiology Group, IBMC - Institute for Molecular and Cell Biology, University of Porto, 4150-180, Porto, Portugal. [email protected].
PMID: 28583160 DOI: 10.1186/s12974-017-0891-9
Abstract

Background: Increasing 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.

Methods: In 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.

Results: We 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.

Conclusion: Altogether, 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.

Keywords

Cathepsin E; Familial amyloidotic polyneuropathy; Immune regulation; Macrophages; Neurodegeneration; Transthyretin.

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