The role of CYLD in macrophages

Thesis

Macrophages are essential components of our innate immune system involved in several biological processes, including sensing and clearance of invading pathogens. IFN-“ is a required cytokine to promote macrophage activation. The regulation of this signalling pathway is therefore crucial for successful pathogen clearance and for the engagement of the adaptive immunity.

The aim of this study was to investigate the role of the deubiquitinase CYLD in macrophage activation. CYLD is a negative regulator of the NF-ŸB signalling pathway. Consistent with this, CYLD-deficient mice present higher production of pro-inflammatory cytokines and increased clearance when challenged with pathogens. However, the molecular mechanisms and the role of macrophages underlying this protective process have not yet been investigated.

I identified CYLD to regulate and be regulated by the IFN-“ signalling pathway. CYLD regulation of the IFN-“ signalling pathway occurs through its deubiquitinase activity. In line with this, CYLD-depleted macrophages present an enhanced IFN-“ transcriptional response, with upregulation of genes involved in macroautophagy and xenophagy, such as NOD2, RIPK2 and OPTN. Furthermore, these cells display an increased phagocytic and lysosomal activity, as well as higher autophagic flux. Deregulation of the IFN-“ signalling pathway leads to an enhanced ability to restrict intracellular gram-positive and gram-negative bacteria growth in CYLD-depleted macrophages. This novel role of CYLD provides insight into the regulation of macrophage activation, where CYLD directly controls NF-ŸB and IFN-“ cellular responses and resultant macrophage functions.

Authors: Zucca, M

• DOI: 10.5287/ora-zojxnrjyp
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford