Understanding how injured tissue communicates with the immune system

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Abstract

Inflammation in the absence of infection (sterile inflammation) is a crucial host defence response to tissue injury, but is also considered to contribute to the pathogenesis of many diverse disease states, including stroke. Sterile inflammation is initiated by damage associated molecular patterns (DAMPs) which are endogenous molecules released from necrotic cells or that are modified during disease. The pro-inflammatory cytokines IL-1α and IL-1β are key mediators of inflammation. IL-1β release is controlled by caspase-1 which, in turn, is regulated by the inflammasome. The NOD-, LRR-, pyrin domain-containing 3 (NLRP3) inflammasome is most typically associated with sterile inflammation and the recognition of DAMPs. Thus, understanding the mechanisms of NLRP3-activating DAMP-induced inflammation may lead to the identification of novel therapeutic targets with which to treat inflammatory diseases. This thesis sought to determine how NLRP3-activating DAMPs affect the pro-inflammatory response of glia, the immune cells of the brain.Experimental models in vitro typically use a pathogen associated molecular pattern (PAMP) such as LPS to prime cells before observing their response to NLRP3-activating DAMPs. As the brain is protected by the blood brain barrier (BBB), it is unlikely glia would be exposed to PAMP priming. However it remains unclear as to how glia respond to NLRP3-activating DAMPs in the absence of priming, or what the source of endogenous priming is. Therefore, the initial hypothesis was to investigate the pro-inflammatory response of mixed glia in vitro to NLRP3-activating DAMPs in the absence of PAMP priming. It is shown here for the first time that NLRP3-activating DAMPs can initiate an IL-1-NLRP3-independent inflammatory response in mixed glia in the absence of PAMP priming. Moreover, it is shown that the acute phase protein serum amyloid A is elevated in plasma after stroke and may act as an endogenous priming signal to allow IL-1β-dependent inflammation to contribute to the damage after breakdown of the BBB.Inflammation following acute sterile injury such as stroke is augmented by persisting cell death. It was therefore hypothesised that NLRP3-activating DAMPs released after the initial injury, may initiate a form of programmed cell death that continues to drive inflammation. Using inhibitors of specific types of cell death, it was identified that NLRP3-activating DAMP induced cell death is likely to be necrosis and not programmed cell death.Further investigation into the biological importance of DAMP-induced IL-1-independent inflammation and the specific contribution of acute phase proteins to brain pathology may aid the identification of new therapeutic targets.

Keyword(s)

Cerebral ischaemia; DAMPs; Interleukin-1; Sterile inflammation

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