Immunomodulation of the NLRP3 Inflammasome through Structure-Based Activator Design and Functional Regulation via Lysosomal Rupture.

Autor:	Manna S; Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States.; Institute for Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States., Howitz WJ; Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States., Oldenhuis NJ; Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States., Eldredge AC; Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States., Shen J; Institute for Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States., Nihesh FN; Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States.; Institute for Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States., Lodoen MB; Department of Molecular Biology and Biochemistry and The Institute for Immunology, University of California, Irvine, Irvine, California 92697, United States., Guan Z; Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States., Esser-Kahn AP; Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States.; Institute for Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2018 Aug 22; Vol. 4 (8), pp. 982-995. Date of Electronic Publication: 2018 Jul 02.
DOI:	10.1021/acscentsci.8b00218
Abstrakt:	The NLRP3 inflammasome plays a role in the inflammatory response to vaccines, in antimicrobial host defense, and in autoimmune diseases. However, its mechanism of action remains incompletely understood. NLRP3 has been shown to be activated by diverse stimuli including microbial toxins, ATP, particulate matter, etc. that activate multiple cellular processes. There have been two major challenges in translating inflammasome activators into controlled adjuvants. Both stem from their chemical and structural diversity. First, it is difficult to identify a minimum requirement for inflammasome activation. Second, no current activator can be tuned to generate a desired degree of activation. Thus, in order to design such immunomodulatory biomaterials, we developed a new tunable lysosomal rupture probe that leads to significant differences in inflammasome activation owing to structural changes as small as a single amino acid. Using these probes, we conduct experiments that suggest that rupturing lysosomes is a critical, initial step necessary to activate an inflammasome and that it precedes other pathways of activation. We demonstrate that each molecule differentially activates the inflammasome based solely on their degree of lysosomal rupture. We have employed this understanding of chemical control in structure-based design of immunomodulatory NLRP3 agonists on a semipredictive basis. This information may guide therapeutic interventions to prevent or mitigate lysosomal rupture and will also provide a predictive framework for dosable activation of the NLRP3 inflammasome for potential applications in vaccines and immunotherapies. Competing Interests: The authors declare no competing financial interest.
Databáze:	MEDLINE
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