Un phénotype immunitaire dans les souris PC1/3 KO un rôle régulateur de PC1/3 dans la sécrétion de cytokines

Abstract

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.