BICTEL/e - ULg
Serveur institutionnel des thèses de doctorat

• XIAP
• inositol phosphatase
• NOD2
• innate immunity/immunité innée

Innate immunity constitutes the first line of host defence against pathogens. It activates inflammation and initial antimicrobial responses prior to the onset of adaptive immunity. Recognition of invading pathogens is a crucial mechanism that relies on recognition of pathogen-associated molecular patterns (PAMPs) by patterns recognition receptors (PRRs). The PRR armada is composed of the membrane-associated toll-like receptors (TLRs) that sense pathogens at cell surface and within the endosomes whereas the cytosolic NOD-like receptors (NLRs) guard the intracellular compartment. NLRs, such as NOD1 and NOD2, are able to induce cytokines, chemokines and antimicrobial peptides production by activating the transcription factor nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). Essential role for NOD2 in immunity is highlighted by the fact that mutations in the NOD2 gene are associated with increased risk to develop Crohn’s disease, a chronic inflammatory bowel disease.

SHIP-1 is an SH2-containing inositol 5’-phosphatase principally expressed by hematopoietic cells. Over the past decade, SHIP-1 has been described as an important regulator of immune functions. For instance, SHIP-1 downregulates B cells activation and mast cells degranulation. Strikingly, SHIP-1 is a downmodulator of TLRs signaling. Indeed, SHIP-1 KO macrophages exhibit an increased cytokines production in response to TLR4 triggering and produce more interferon β in response to TLR3 activation than their WT counterpart. The inability of SHIP-1-deficient mice to control TLR activation has a dramatic consequence, as these mice fail to develop an endotoxin tolerance.

Considering the similarity of TLRs and NLRs signaling pathways, this work has investigated the function of SHIP-1 in the negative regulation of the NLR receptors, i.e. NOD1 and NOD2. We have established that SHIP-1 downregulates both NOD1 and NOD2-induced NF-κB activation. This property relies on its interaction with XIAP. Indeed, we have observed that XIAP is an essential mediator of the NOD1 and NOD2 signaling pathway that enables proper NF-κB activation in macrophages. Mechanistically, we defined that, upon NOD2 activation, SHIP-1 interacts with XIAP, thereby disturbing the interaction between XIAP and RIP2 in order to decrease NF-κB signaling.

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