Investigating fundamentals of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer
Innate immunity is the first line of defense against infectious disease. The resulting inflammation is the first response to infection and injury. Pathogen sensing and signaling in innate immune and barrier cells drive inflammation to combat infection. Excessive or chronic inflammation can contribute to the development of many diseases including autoimmune disorders and cancer. Our laboratory seeks to gain fundamental insight into innate immune mechanisms to identify novel processes and new molecular targets. This will inform the development of therapeutic strategies.
Our laboratory is known for fundamental discoveries elucidating functions of innate immune receptors, inflammasomes, and inflammatory cell death. As a founding member of the inflammasome field, we continue to make critical contributions to this research area. The inflammasome, a multimeric protein complex, is a critical component of the innate immune response. Inflammasomes sense pathogen- and damage-associated molecular patterns to initiate inflammatory immune responses and drive pyroptosis, a form of programmed cell death. While cell death is essential for organismal development, dysregulation often leads to disease.
We provided the first genetic evidence for the role of the innate immune receptor NLRP3 in microbial-mediated inflammasome activation. We also established the importance of the NLRP3 inflammasome in intestinal inflammation, neuroinflammation, cancer, and metabolic diseases. We have continued to provide innumerable insights to drive the maturation of this field into a major research area by identifying key components and regulatory mechanisms of inflammasome pathways and discovering their biological and physiological functions. Beyond our work on the NLRP3 inflammasome and cell death pathways, we have identified the activation mechanisms of other inflammasomes including NLRC4, NLRP1, PYRIN, and AIM2 in infection, inflammatory disease, and cancer. Additionally, we have characterized other key innate sensing pathways and described distinct, novel roles for IL-1α, IL-1β, and IL-33 in disease.
These studies on inflammasomes/pyroptosis led to a pivotal breakthrough in the cell death research area. While several cell death pathways had been previously characterized that were thought to be distinct, independent pathways, we and others performed genetic, molecular and biochemical studies that identified extensive crosstalk among the molecular components across cell death pathways in response to a variety of pathogens and innate immune triggers. These studies highlighted a key gap in our understanding of cell death and led us to establish the fundamental concept of PANoptosis and this new field of research.
PANoptosis is a unique innate immune inflammatory cell death pathway that is driven by caspases and RIPKs and is regulated by multiprotein PANoptosome complexes. We identified ZBP1 as the first innate immune sensor to form a PANoptosome and induce PANoptosis. Building on this initial discovery, our work has elucidated several infectious agents, cytokine signaling pathways, and inflammatory syndromes that activate PANoptosis, implicating this process in infectious and autoinflammatory diseases, cancer, and beyond. To date, we have identified four PANoptosome complexes, the ZBP1-, RIPK1-, AIM2-, and NLRP12-PANoptosomes, and described their roles in disease. Additionally, we have found that IRF1 is a key upstream regulator required for PANoptosis activation by PANoptosomes. Furthermore, we recently discovered that TNF and IFN-γ released during disease, specifically during COVID-19, drive PANoptosis to induce further cytokine release, tissue damage, and death, providing the first mechanistic definition for cytokine storm. PANoptosis is now implicated in driving innate immune responses and inflammation across the disease spectrum.
Overall, with more than 340 manuscripts, all focused on innate immunity, inflammasomes, and cell death, our studies have contributed to both the inception and the maturation of the inflammasome field as a major research area in immunology and inflammation research, advanced our understanding of cell death pathways, progressed new therapeutics, and identified novel applications for existing drugs.