IL-1/IL-1RI signaling is pivotal for driving dysregulation of homeostasis in normal tissues through inflammation, a process of recruitment and retention of specialized cells of hematopoietic origin, which may and often does lead to the disruption of physiological function of the affected organ. Today, the pathogenesis of the vast majority of human diseases has been linked to the acute or chronic inflammation as the key components of homeostatic dysregulation, mechanistically underlying numerous and specific disease-driving pathologies. IL- 1RI signaling is initiated upon binding of either of two principal non-homologous ligands of the receptor ? IL-1? or IL-1?. Over the past decade, truly remarkable progress has been made in understanding the biology of IL-1? due to the discovery of the caspase-1-dependent inflammasome(s) and caspase-8 as regulators of IL-1? biogenesis. In stark contrast to IL-1?, and despite being the first major human pyrogen described (Dinarello et al., 1974), the biogenesis of IL-1? remains poorly understood. Furthermore, despite increasing appreciation of the contribution of IL-1? in the pathogenesis of many important human diseases, the factors that control functional IL-1? maturation remain completely obscure. The goal of this exploratory grant proposal is to identify specific molecular modifications of IL-1? precursor that enable physiological IL-1? function in its membrane- bound and secreted forms.
In Specific Aim 1, we will define the functional role of specific post-translational modifications of pro-IL-1? for eliciting IL-1? biological activity as secreted and membrane-bound cytokines in vitro.
In Specific Aim 2, we will define molecular forms of IL-1?, triggering inflammatory IL-1RI signaling in response to viral and bacterial pathogens and cytotoxic injury in vivo. These studies should aid in developing a unifying conceptual model of biogenesis of IL-1? that enables protective and pathologic IL-1?-driven host responses to pathogens, stress, and sterile injury. These studies have the potential to shift the currently- accepted IL-1?-centric paradigm of inflammation to a concept of IL-1?-dependent pro-inflammatory priming at a site of injury or infection as the initiator and sustainer of inflammation underlying a great number of human diseases.
/ PUBLIC HEALTH RELEVANCE Interleukin-1 (IL-1) is a major mediator of systemic and local inflammation. A rapidly growing number of diseases including obesity, cardiovascular disease, diabetes, cancer and many systemic autoimmune and auto-inflammatory conditions, has been directly linked to pro-pathologic function of IL-1, and IL-1 receptor type I (IL-1RI) signaling has been implicated as the principal molecular basis to the initiation and/or maintenance of the disease-underlying pathology. At present we have no understanding of how IL-1? activity is regulated to induce IL-1RI signaling from the plasma membrane or as a secreted cytokine from alive, non-pyroptotic and non-necrotic cells. This exploratory proposal is to fill the major void in our understanding of the role of specific post-translational modification of pro-IL-1? that control IL-1? biological activity in vitro and in vivo. The proposed studies will provide new mechanistic insights into fundamental cellular and molecular biological processes related to pro-inflammatory IL-1? function, and have the potential to aid in identification of novel potential therapeutic targets to tame unwarranted severe and/or pathologic inflammation that is mechanistically linked to dysregulated IL-1/IL-1RI signaling.
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