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Pathophysiology of Immune-Related Complications in Lysinuric Protein Intolerance

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Pathophysiology of Immune-Related Complications in Lysinuric Protein Intolerance Pathophysiology of immune-related complications in Lysinuric Protein Intolerance Fernando Sotillo Rodríguez Aquesta tesi doctoral està subjecta a la llicència Reconeixement- NoComercial – SenseObraDerivada 3.0. Espanya de Creative Commons. Esta tesis doctoral está sujeta a la licencia Reconocimiento - NoComercial – SinObraDerivada 3.0. España de Creative Commons. This doctoral thesis is licensed under the Creative Commons Attribution-NonCommercial- NoDerivs 3.0. Spain License. Barcelona, 2017 – Universitat de Barcelona Facultad de Farmacia i Cièncias de l’alimentació Programa de Doctorat en Biomedicina Pathophysiology of immune-related complications in Lysinuric Protein Intolerance Memoria presentada por Fernando Sotillo Rodríguez para optar al título de doctor por la Universitat de Barcelona Directores Doctorando Manuel Palacín Susanna Bodoy Fernando Sotillo Barcelona, Diciembre 2017 A mi familia, por el apoyo, por la educación. 3 Quiero agradecer a... Manuel y Susanna, Susanna y Manuel, mis dos codirectores. Tan diferentes y tan necesarios. Pasión y realismo, la pizarra llena de flechas y la fulla amb el que s’ha de fer, del “si esto no se puede hacer, no habríamos descubierto América” al “si sortís tot el que fem, publicaríem un Nature cada mes”. Muchas gracias por la tremenda oportunidad que me habéis dado, por todo lo que me habéis enseñado y por todo lo que me habéis transmitido. No solo me habéis hecho descubrir lo maravillosa que es la ciencia, también he aprendido que lo importante no es como empieza sino como acaba, que lo concreto te conduce hasta lo general y que toda buena historia se compone a base de pequeñas piezas. De verdad, gracias. Sara, compañera de tesis para la eternidad. De hecho, no me puedo imaginar una compañera mejor que tú. Contigo hemos bebido, hemos reído, he aprendido, he disfrutado, pero sobre todo, hemos rajado! Ha sido brutal tenerte al lado estos años. Y si hablamos de rajar, ahí están las dos gurús, las dos maestras, Aida y Alba, criminal equipo titular. El resto de Palacines, los defensores de la estructura. Por un lado Albert y su templanza para adaptarse a quién tenga al lado, desde Ana hasta Paloma pasando por Elena. Y por el otro la dolce Paola, Joana, dempeus sempre y Ekaitz. Y por supuesto, importantísima, la última invitada al LPI team, Judith; espero que además de a preparar aminoácidos, hayas aprendido que lo importante no es hablar mucho, si no hablar bien ;) (ya estabas suficientemente preparada como para poder hacer el máster en Madrid). Los Zorzanos por su ayuda y compañía, Saska, Maribel, Montse, David, Manu, Yuli y muy especialmente a JP. JP y Jordi (al becario también) porque sin él sería un poco menos JP, y el lab un auténtico caos. También a Olga, Natalia Molner y Natalia Plana. Y cómo no a Jordi Durán, el MVP del TAC. Patrizia, Álvaro, Sonia, Pablo, Eric, Iris y Clara porque no habría llegado al IRB de no haber pasado por el IDIBELL. Y al IDIBELL no habría llegado de no haber pasado por El 12, así que también gracias a Julia (por el enchufe) y a Ana (por el relevo). Al Mossack (y a algunos no Mossack) por convertir cada coñazo en pura carcajada, por tantos años, por tantos momentos. A Bea por la pedazo de portada. Al bueno de Dani Fransi, pilar fundamental desde Leuven y a Isa, pilar fundamental desde el tuto, que después de ser Villarriba, han pasado a ser familia. I per descomptat a l’Ester, que és més que família, és companya, és mestra, és suport, és consell… en definitiva, és el que calgui en cada moment. … a todos vosotros, por todo ello, GRACIAS. Un pedacito de esta tesis es vuestro. 5 7 8 TABLE OF CONTENT TABLE OF CONTENT -------------------------------------------------------------------------------------------------- 9 INTRODUCTION ----------------------------------------------------------------------------------------------------- 13 Amino acid transport and disease -------------------------------------------------------------------------- 15 Heteromeric Amino Acid Transporters ------------------------------------------------------------------ 15 Transport of cationic amino acids ------------------------------------------------------------------------ 16 Lysinuric Protein Intolerance --------------------------------------------------------------------------------- 20 Pulmonary Alveolar Proteinosis -------------------------------------------------------------------------- 25 Pulmonary Alveolar Proteinosis in Lysinuric Protein Intolerance: -------------------------------- 27 Hemophagocytic lymphohistiocytosis ------------------------------------------------------------------- 29 Hemophagocytic lymphohistiocytosis in Lysinuric Protein Intolerance ------------------------- 31 Macrophages ----------------------------------------------------------------------------------------------------- 32 Principles of immunity -------------------------------------------------------------------------------------- 32 Amino acid control of immunology ---------------------------------------------------------------------- 33 Macrophage populations ---------------------------------------------------------------------------------- 34 L-Arginine metabolism in macrophages ---------------------------------------------------------------- 36 Nitric Oxide Synthases -------------------------------------------------------------------------------------- 37 Nitric Oxide in Lysinuric Protein Intolerance ----------------------------------------------------------- 38 Arginase 1 ------------------------------------------------------------------------------------------------------ 39 Iron metabolism ------------------------------------------------------------------------------------------------- 40 Erythropoiesis ------------------------------------------------------------------------------------------------- 41 Iron transport and storage--------------------------------------------------------------------------------- 42 Iron metabolism in macrophages ------------------------------------------------------------------------ 45 OBJECTIVES ---------------------------------------------------------------------------------------------------------- 49 METHODS ------------------------------------------------------------------------------------------------------------ 54 Animals ------------------------------------------------------------------------------------------------------------ 57 Metabolic cages ---------------------------------------------------------------------------------------------- 58 Slc7a7-/- mouse model: -------------------------------------------------------------------------------------- 60 Genotyping: --------------------------------------------------------------------------------------------------- 62 Protein protocols ------------------------------------------------------------------------------------------------ 64 ELISA ------------------------------------------------------------------------------------------------------------ 64 Membrane purification and protein extraction ------------------------------------------------------- 65 Western Blot -------------------------------------------------------------------------------------------------- 66 Gene expression ------------------------------------------------------------------------------------------------- 67 RNA extraction ------------------------------------------------------------------------------------------------ 67 RT-PCR ---------------------------------------------------------------------------------------------------------- 71 qRT-PCR -------------------------------------------------------------------------------------------------------- 71 Microarray ----------------------------------------------------------------------------------------------------- 75 Isolation of murine macrophages --------------------------------------------------------------------------- 77 11 Alveolar macrophages -------------------------------------------------------------------------------------- 78 Splenic Red Pulp macrophages --------------------------------------------------------------------------- 78 Bone Marrow Derived Macrophages -------------------------------------------------------------------- 80 Histology and cytology ----------------------------------------------------------------------------------------- 82 Histology ------------------------------------------------------------------------------------------------------- 82 Cytology -------------------------------------------------------------------------------------------------------- 84 Non-heme iron tissue quantification ----------------------------------------------------------------------- 84 In vitro assays ---------------------------------------------------------------------------------------------------- 84 Nitric Oxide ---------------------------------------------------------------------------------------------------- 84 Erythrophagocytosis Assay -------------------------------------------------------------------------------- 85 Erythropoiesis analysis ----------------------------------------------------------------------------------------- 86 RESULTS --------------------------------------------------------------------------------------------------------------- 87 Previous results of the group --------------------------------------------------------------------------------- 89 Immune-related complications in LPI ---------------------------------------------------------------------- 93 Slc7a7-/- mouse model develops Pulmonary Alveolar Proteinosis --------------------------------
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