Monday, April 29, 2024
4/29/2024
Project Summary The IL-1 subfamily members IL-1a and IL-1ß both signal through the IL-1R1 receptor. The activation and function of IL-1ß has been described extensively in the context of inflammasome activation, which culminates in active caspase-1 cleaving inactive pro-IL-1ß to its active and secreted form. While pro-IL-1a can also be cleaved and secreted by inflammasome activation, in contrast to IL-1ß, pro-IL-1a is biologically active and is constitutively expressed in epithelial cells. IL-1a exhibits dual functionality, acting as a traditional cytokine but also controlling a number of diverse cellular functions. As discussed in this proposal, we have identified novel and physiologically relevant functions of IL-1a in the context of innate immunity and inflammation, however the mechanisms by which they are regulated is unclear. These novel findings reveal a number of fundamental knowledge gaps in our understanding of IL-1a biology. In particular, the pathways by which IL-1a is released from dying cells are largely unknown as is its ability to regulate inflammatory and cell death pathways. We will utilize crystalline silica as a sterile inflammatory insult to interrogate these mechanistic questions. We have found that IL-1a in non- hematopoietic cells plays a role in the recruitment of neutrophils to the lung in response to a sterile inflammatory insult. Further, we show in vitro that IL-1a can bind specifically to the phospholipids cardiolipin and phosphatidylserine. In epithelial cells, IL-1a co-localizes with phosphatidylserine and IL-1a is externalized coincident with the movement of phosphatidylserine to the outer surface of the cell during apoptosis. Phosphatidylserine exposure is an established “eat me” signal that identifies apoptotic cells for clearance by macrophages through efferocytosis. We have found the presence of IL-1a on the surface of the cell blocks efferocytosis, and propose this failure results in secondary necrosis of the epithelial cells, release of DAMPs, and a physiologically relevant enhancement of inflammatory responses. Finally, we show the binding of IL-1a to cardiolipin, once externalized on the mitochondrion by mitochondrial dysfunction, blocks the removal of damaged mitochondria by mitophagy. We propose IL-1a binding to cardiolipin blocks its recognition by LC3b, a critical step in mitophagy, thus preventing removal of damaged mitochondria. It is known that activation of the Nlrp3 inflammasome is triggered by mitochondrial damage and that downregulation of mitophagy results in enhanced Nlrp3 inflammasome activation. We further propose that intracellular pro-IL-1a enhances Nlrp3 activation by blockade of mitophagy. The completion of these studies will provide important insights into the regulation of the innate immune response by the multiple cellular functions of IL-1a.
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