IL-36 member activation and secretion, and their role in immune defence

The IL-36 cytokines are a recently identified subset of the IL-1 superfamily that are becoming firmly established as instigators of pathogenic inflammation in a number of inflammatory conditions. IL-36γ, in particular, has been strongly linked to psoriatic inflammation of the skin. As with many IL-1 proteins, the IL-36 cytokines must undergo post-translational truncation in order to become biologically active, however the manner in which this occurs and their subsequent release from cells is poorly understood. Furthermore, research into these questions is greatly hindered by the lack of available IL-36 specific antibodies. This work has therefore focused on 1) producing IL-36γ specific monoclonal antibodies to facilitate further IL-36 research, 2) the post-translational processing by endogenous and exogenous proteases, 3) the physiological role of IL-36 in epithelial barrier homeostasis. The results of this work include successful production and characterisation of 4 anti-IL-36γ monoclonal antibodies and subsequent development of an IL-36γ ELISA that has been used to identify IL-36γ as a reliable psoriasis specific disease marker. Secondly, an epithelial protease, cathepsin S, has been identified as able to cleave and activate IL-36γ and has been shown to be widely expressed within the skin compartment. Furthermore, it has identified that exogenous proteases produced by the opportunistic pathogen Aspergillus fumigatus are capable of cleaving and activating IL-36γ to initiate IL-36-mediated inflammation. Finally, IL-36γ was shown to promote epithelial barrier function by enhancing epithelial proliferation and providing resistance against apoptosis, which may be indicative of a role in wound healing. Overall from these findings we propose that the IL-36 cytokines may act as sensors of epithelial damage in response to protease-dependant activation that play a prominent role in the first line of defence against invading pathogens.