The NLRP3 inflammasome is essential for the production of IL-1? and other pro-inflammatory mediators, and as such is critical in elaborating inflammation in a variety of settings, including infectious diseases, autoinflammatory diseases, and complex diseases characterized by pathological inflammation. In many such diseases, the etiologic agent has been shown to instigate inflammation in a NLRP3 inflammasome-dependent manner. Examples include extracellular ATP released from dying cells, uric acid crystals that accumulate during arthritis, cholesterol crystals in atherosclerotic plaques, various bacterial toxins, and misfolded protein aggregates linked to neurodegenerative diseases. How these diverse molecules activate the NLRP3 inflammasome is not known, and our recent studies implicate a critical role for Calcium (Ca2+) signaling. In this proposal we aim to further elucidat how Ca2+ mobilization regulates activation of the NLRP3 inflammasome, uncover new regulators of the pathway, and integrate current models into one unifying model. This effort would advance basic research in the inflammasome field and identify novel targets for treating the many diseases linked to NLRP3 inflammasome activation.
Understanding how inflammation is triggered is critical for therapeutic intervention in diseases characterized by pathophysiological inflammation, including rare autoinflammatory diseases as well as common diseases such as arthritis, atherosclerosis, and diabetes. Here we seek to elucidate mechanisms that regulate activation of a critical inflammatory pathway implicated in such diseases. We expect that successful completion of this work would reveal one central underlying mechanism that could be targeted therapeutically, with the potential to significantly impact public health.
|Covarrubias, Anthony J; Aksoylar, Halil Ibrahim; Yu, Jiujiu et al. (2016) Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Elife 5:|
|Covarrubias, Anthony J; Aksoylar, H Ibrahim; Horng, Tiffany (2015) Control of macrophage metabolism and activation by mTOR and Akt signaling. Semin Immunol 27:286-96|
|Horng, Tiffany (2015) mTOR trains heightened macrophage responses. Trends Immunol 36:1-2|
|Covarrubias, Anthony J; Horng, Tiffany (2014) IL-6 strikes a balance in metabolic inflammation. Cell Metab 19:898-9|
|Yu, Jiujiu; Nagasu, Hajime; Murakami, Tomohiko et al. (2014) Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci U S A 111:15514-9|
|Horng, Tiffany (2014) Calcium signaling and mitochondrial destabilization in the triggering of the NLRP3 inflammasome. Trends Immunol 35:253-61|
|Byles, Vanessa; Covarrubias, Anthony J; Ben-Sahra, Issam et al. (2013) The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 4:2834|
|Covarrubias, Anthony; Byles, Vanessa; Horng, Tiffany (2013) ROS sets the stage for macrophage differentiation. Cell Res 23:984-5|