Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

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The proprotein convertases (PC) are endoproteolytic enzymes essential for the generation of bioactive peptides.The production of KO mice for some of these PCs has allowed us to identify many different physiological phenotypes for these enzymes. PC1/3 is traditionally classified as a neuroendocrine enzyme. This has been supported by many studies performed in PC1/3 KO mice, as well as human subjects deficient in PC1/3, where this enzyme is responsible for the cleavage of neuroendocrine substrates, namely POMC and pro-insulin. However, very little research has been done on the potential role of PC1/3 in the immune system, despite evidence of its expression in immune cells, including macrophages. In the present study, we investigate the PC1/3 KO mouse through an immunological aspect. Our laboratory has previously reported an increase in the expression of PC1/3 in the spleen following LPS stimulation. By examining closely the spleen, we observed a splenomegaly of the organ as well as a marked disorganization of the regions of the spleen, such as an invasion of the red pulp with the marginal zone, which may affect the proper immunological response. Labeling of different immune cells demonstrated a decrease in the dendritic cells present in the PC1/3 KO mouse spleen. An interesting phenotype that was observed in the PC1/3 KO mice is their sensitivity to an LPS-induced septic shock, which was evident by an exaggerated secretion of pro-inflammatory cytokines (IL-6, IL-1[bêta] et TNF-[alpha]). Furthermore, the present study identifies the macrophages as major contributors to the unbalanced secretion observed in the PC1/3 KO mice since we report an increase in cytokine secretion in isolated peritoneal macrophages. We also demonstrate a link with the adaptive immune system. A massive secretion of IFN-[gamma] was measured in the PC1/3 KO mouse plasma, supporting the notion that the Th1 pro-inflammatory pathway is predominant in these mice following an LPS challenge. Taking into account these results, the study presented identifies a novel and unconventional role of PC1/3 in the regulation of the innate immune system.

Das PCSK1-Gen kodiert für die Prohormonkonvertase 1/3 (PC1/3), einem Enzym, welches eine wichtige Rolle bei der Aktivierung von Prohormonen in ihre aktive Form spielt. Unter den Substraten der PC1/3 befinden sich Proinsulin, Proglukagon, Pro-POMC und andere Schlüsselmetabolite des Energiestoffwechsels. In genomweiten Assoziationsstudien wurde eine Korrelation zwischen Varianten in PCSK1 und Übergewicht gefunden. In Einzelfällen führte eine genetische bedingte PC1/3-Defizienz zu einem multiendokrinologischen Krankheitsbild mit schwerer Adipositas. Für einige der Varianten in PCSK1 wurde eine Retention im endoplasmatischen Retikulum (ER) gefunden. Retention im ER, ausgelöst durch fehlgefaltete Proteine, verursacht ER-Stress, welcher ggf. zu Apoptose führen kann. In dieser Arbeit wurde untersucht, ob 5 ausgewählte PCSK1-Varianten die Enzymreifung/-sekretion beeinträchtigen, ob ER-Stress induziert wird und letztlich, ob Apoptose induziert wird. Es fand sich für 2 Varianten eine Retention im ER und eine Induktion von ER-Stress. Apoptose wurde durch keine der untersuchten Varianten induziert.:Abkürzungsverzeichnis 1. Einführung und Hintergrund 1.1 Prohormonkonvertase 1/3 1.1.1. Entstehung und Reifung der Prohormonkonvertase 1/3 1.1.2. Substrate der Prohormonkonvertase 1/3 1.1.3. Prohormonkonvertase 1/3-Defizienz und Krankheitsbilder 1.1.4. Die untersuchten PCSK1-Varianten 1.2. Stress im endoplasmatischen Retikulum und Unfolded protein response 1.3. Ableitung der Rationalen 2. Publikation 3. Zusammenfassung Literaturverzeichnis A. Anhang A.1. Supplemental Information A.2. Methoden A.3. Darstellung des eigenen wissenschaftlichen Beitrags A.4. Erklärung über die eigenständige Abfassung der Arbeit A.5. Lebenslauf A.6. Liste der Veröffentlichungen A.7. Danksagung

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The sediment Core SWERUS-L2-2-PC1 (2PC) retrieved from the Chukchi Sea, Arctic Ocean sits in an oceanographically dynamic location at the Arctic-Pacific Ocean gateway. The 8.3 m-long core was retrieved in Herald Canyon at the marginal ice zone at 57 m depth. Core 2PC is well-positioned to record variability in inflow of Bering Sea Water (BSW) and Pacific Water (PW) in Herald Canyon. With the 2PC high sedimentation rate (200 cm/kyr), two independent age models (radiocarbon and palaeomagnetism) based on tephra age markers, and a richness in well-preserved siliceous sediment, validate 2PC as an outstanding sequence for applying diatom assemblage analysis as a proxy for ocean-climate change back to 4250 years BP, including the past few hundred years where global warming and sea ice decline is recorded by instrumental records. These characteristics make Core-2PC a useful record for investigating the role of PW on sea ice variability in the Chukchi Sea, both in the past and predicting the future. To investigate the impact of PW on ocean and sea ice conditions in the Chukchi Sea, diatom assemblage analysis was performed on 49 samples through the Late Holocene. The over-arching goal was to test the hypothesis, suggested by existing research on 2PC using benthic foraminifera Mg/Ca palaeothermometry, that the strength of PW inflow into the Chukchi Sea via Herald Canyon has varied on a time scales of ~500-1000 years in the past 4000 years. PW is slightly warmer than resident Arctic surface waters and is known to be an important control on Arctic sea-ice. The diatom assemblage approach assumes that there are recognizable differences between end-member diatom assemblages that are characteristic of PW versus Arctic Ocean type environments associated with extensive sea-ice conditions. The mapping of species in the Herald Canyon was used to test the idea of variability of sea-ice extent and the role of the Pacific Ocean forcings into the western Chukchi Sea. The results reveal diverse diatom assemblages throughout the past 4000 years in Herald Canyon, showing this core to be very useful for diatom palaeoclimate reconstructions. A total of 126 species with abundance >1% are recognized. Several generalist species typically dominate assemblages especially Chaetoceros, ice-algae, marine-neritic and near ice or cold-water planktic centric diatoms. Distinct changes in stratigraphy are illustrated by changes in identified diatom assemblage zones. The 2PC diatom assemblages were contrasted with records from Chukchi-, Laptev-, East Siberian- and Bering Sea and North Pacific Ocean. At 2PC, sympagic (sea-ice related), planktic and neritic species abundance varies on time scales of ~500-1000 years. Importantly, there is a clear similarity between the timing of diatom assemblage changes and the 2PC benthic foraminifera Mg/Ca bottom water temperature (BWT) reconstruction. In particular, abundance changes in the warm water species Thalassionema nitzschioides, Shionodiscus oestrupii and Thalassionema simonsenii, tychoplanktic Paralia sulcata, Ice algae- and sympagic assemblages and cold-water indicators correspond best to BWT fluctuations shown by the Mg/Ca reconstruction. These oscillations are suggestive of changes in warmer PW inflow. Other aspects of the diatom data appear to correlate with colder and warmer climate events and suggest that changes in PW inflow amplified the effects of these events in the Chukchi Sea region through the Late Holocene in the Northern Hemisphere. It can thus, be concluded that diatoms from 2PC, support the palaeoceanographic reconstruction suggested by the benthic foraminifera Mg/Ca palaeothermometry and that variations in PW inflow through Herald Canyon is an important driver of sea ice variability on thousand-year time scales.