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

ACS Central Science
Saikat MannaAaron P Esser-Kahn

Abstract

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 ru...Continue Reading

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Citations

Jun 23, 2020·Mediators of Inflammation·Hui SunJia-Lin Gao
Nov 21, 2018·Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology·Emma ShardlowChristopher Exley
Oct 13, 2020·The Journal of Cell Biology·Paula I SeoaneDavid Brough
Mar 12, 2021·Advanced Functional Materials·Shannon J TsaiChristopher M Jewell
Jul 3, 2021·International Journal of Molecular Sciences·Christine Péladeau, Jagdeep K Sandhu
Feb 16, 2019·Journal of the American Chemical Society·Sampa MaitiWenjun Du
Sep 12, 2020·Chemical Reviews·Wen-Hao Li, Yan-Mei Li
Aug 31, 2018·ACS Central Science·Pamela V Chang, Catherine L Grimes
Sep 21, 2021·ACS Applied Materials & Interfaces·Dipika NandiAshish Kulkarni
Nov 18, 2021·Biomacromolecules·Zhiyuan FanZhibin Guan
Nov 10, 2020·Acta Pharmaceutica Sinica. B·Aqu AluXiawei Wei

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Methods Mentioned

BETA
dynamic light scattering
confocal microscopy
flow
ELISA
flow cytometry

Software Mentioned

Zen
Amnis IDEAS
ImageStream
INSPIRE

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