The Nlrp3 inflammasome has been linked to both protective and pathologic immune responses. Its appropriate activation triggers the innate immune response to invading pathogens including influenza virus, Staphylococcus aureus and Candida albicans and its excessive response underlies the autoinflammatory syndromes CAPS (cryopyrin associated periodic syndromes). The Nlrp3 inflammasome is also triggered by abnormal metabolic conditions that lead to the development of common debilitating disorders such as gout, type II diabetes mellitus and atherosclerosis. We have identified a novel step in the pathway by which the Nlrp3 inflammasome is activated that reveals a previously unrecognized overlap with the activation of extrinsic apoptotic pathways. Preliminary studies in our lab show that similar to these apoptotic pathways Nlrp3 inflammasome activation induces mitochondrial dysfunction as demonstrated by a loss of the normal negative potential within the mitochondria. During apoptosis this loss of mitochondrial membrane potential is associated with the translocation of the mitochondrial lipid cardiolipin from its location on the inner mitochondrial membrane to the outer membrane. This movement is accompanied by oxidation of cardiolipin and the release of its binding partner, cytochrome c, to the intermembrane space. Cardiolipin on the outer mitochondrial membrane recruits and binds caspase-8 that in turn drives the generation of an outer mitochondrial membrane pore through which cytochrome c, loose from its tether to cardiolipin, crosses to the cytosol and triggers immunologically silent cell death by apoptosis. We now show this requirement for and ability to bind mitochondrial cardiolipin is shared by Nlrp3, previously shown to migrate to the mitochondria during activation. Additionally, the loss of mitochondrial membrane potential, a defining step in apoptosis, is also required for Nlrp3 inflammasome activation. In this proposal we specifically dissect the role of cardiolipin in Nlrp3 activation and determine to what extent Nlrp3 inflammasome activation mirrors apoptosis. These studies will determine the point of divergence of these two pathways, important not only to advance our understanding of this vital inflammatory pathway but also because once identified this switch between pathways may prove to be a target for therapeutic intervention. Manipulation of these pathways is attractive not only for modifying Nlrp3 responses but also for the potential to switch from the apoptotic pathway to an inflammatory one as could be of benefit in the setting of malignancy or covert infections.
Activation of the innate immune response is a critical step in the body's fight against infection and cancer. Immune responses can be excessive as in autoimmune or autoinflammatory conditions or insufficient as in the case of overwhelming infections or invading tumors. Better understanding of the mechanisms that trigger and regulate the innate immune response will allow for smarter and safer therapies for patients suffering from these disorders. We propose to dissect the pro-inflammatory pathway of Nlrp3 inflammasome activation and determine how it differs from the similar but non-inflammatory pathway of apoptosis. Through the illumination of these pathways we can open the door to directed manipulations of these immune responses and achieve improved outcomes for patients.
|Kolb, Ryan; Kluz, Paige; Tan, Zhen Wei et al. (2018) Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4. Oncogene :|
|Elliott, Eric I; Miller, Alexis N; Banoth, Balaji et al. (2018) Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming. J Immunol 200:3047-3052|
|Banoth, Balaji; Cassel, Suzanne L (2018) Mitochondria in innate immune signaling. Transl Res 202:52-68|
|Hornick, Emma E; Banoth, Balaji; Miller, Ann M et al. (2018) Nlrp12 Mediates Adverse Neutrophil Recruitment during Influenza Virus Infection. J Immunol 200:1188-1197|
|Janowski, Ann M; Colegio, Oscar R; Hornick, Emma E et al. (2016) NLRC4 suppresses melanoma tumor progression independently of inflammasome activation. J Clin Invest 126:3917-3928|
|Ulland, Tyler K; Jain, Nidhi; Hornick, Emma E et al. (2016) Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nat Commun 7:13180|
|Ciraci, Ceren; Janczy, John R; Jain, Nidhi et al. (2016) Immune Complexes Indirectly Suppress the Generation of Th17 Responses In Vivo. PLoS One 11:e0151252|
|Kolb, Ryan; Phan, Liem; Borcherding, Nicholas et al. (2016) Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nat Commun 7:13007|
|Cassel, Suzanne L; Janczy, John R; Bing, Xinyu et al. (2014) Inflammasome-independent IL-1? mediates autoinflammatory disease in Pstpip2-deficient mice. Proc Natl Acad Sci U S A 111:1072-7|
|Sutterwala, Fayyaz S; Haasken, Stefanie; Cassel, Suzanne L (2014) Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci 1319:82-95|
Showing the most recent 10 out of 11 publications