Dysregulated IL-1β production has been implicated in a host of disease settings, ranging from autoinflammatory syndromes to diabetes and Alzheimer’s disease. The first-identified interleukin-converting enzyme or ‘ICE’ was caspase-1. The assembly of cytosolic, multi-protein complexes called inflammasomes canonically triggers the activation of caspase-1. Following proximity-induced autocatalysis of procaspase-1 dimers, activated caspase-1 molecules proteolytically catalyze the conversion of the pro-inflammatory cytokines, proIL-1β and proIL-18, into their mature cytokines, IL-1β and IL-18. The coordination of IL-1β cytokine generation is under the regulation of the individual proteins which comprise the particular cytosolic, multi-protein complex.
Caspase-8 has recently emerged as an alternative ICE in response to microbially-induced inflammation for the generation of mature IL-1β and IL-18. My dissertation studies contribute to this rapidly growing field in multiple unique facets. First, in the genetic absence of caspase-1, caspase-8 is recruited to an ASC-containing platform for IL-1β processing in response to nigericin in dendritic cells (DCs). Besides acting as a direct IL-1β convertase, caspase-8 also regulates the activation of caspase-1 induced by nigericin in LPS-primed control DCs, adding an additional layer of complexity to IL-1β regulation. In the context of anti-cancer treatment, the commonly used pro-apoptotic chemotherapeutic drug, doxorubicin (Dox), induces a non-canonical IL-1β processing platform, consisting of RIP1/FADD/caspase-8 and is driven by the downregulation of the cellular inhibitor of apoptosis protein 1 (cIAP1). Enzymatically active caspase-8 then promotes IL-1β maturation within this specific ripoptosome complex. Of particular interest is how this inflammatory signaling pathway may contribute to cancer pathogenesis or amelioration during treatment with Dox.
My data additionally demonstrate the intertwined nature of inflammatory and cell death signaling pathways. The activity of IL-1β convertases, caspase-1 and caspase-8, dictates which mode of cell death a TLR4-primed macrophage/DC will undergo and is highly stimulus-dependent. Consequently, IL-1β signaling is closely associated with pyroptosis when a caspase-1 platform is engaged and apoptotosis when a caspase-8 platform is engaged. Herein this thesis, I discriminate between caspase-1- and caspase-8-based signaling pathways in murine dendritic cells and macrophages for the proteolytic maturation of IL-1β.
