Lipopolysaccharide Primes Human Macrophages for Noncanonical Inflammasome-Induced Extracellular Vesicle Secretion.
Wojciech CyprykLiliana CzernekKatarzyna HorodeckaJędrzej ChrzanowskiMarcin StańczakKatariina NurmiMarcelina BilickaMariusz GadzinowskiAurelia Walczak-DrzewieckaMaria StenslandKari K EklundWojciech FendlerTuula Anneli NymanSampsa MatikainenPublished in: Journal of immunology (Baltimore, Md. : 1950) (2023)
Human macrophages secrete extracellular vesicles (EVs) loaded with numerous immunoregulatory proteins. Vesicle-mediated protein secretion in macrophages is regulated by poorly characterized mechanisms; however, it is now known that inflammatory conditions significantly alter both the quantities and protein composition of secreted vesicles. In this study, we employed high-throughput quantitative proteomics to characterize the modulation of EV-mediated protein secretion during noncanonical caspase-4/5 inflammasome activation via LPS transfection. We show that human macrophages activate robust caspase-4-dependent EV secretion upon transfection of LPS, and this process is also partially dependent on NLRP3 and caspase-5. A similar effect occurs with delivery of the LPS with Escherichia coli-derived outer membrane vesicles. Moreover, sensitization of the macrophages through TLR4 by LPS priming prior to LPS transfection dramatically augments the EV-mediated protein secretion. Our data demonstrate that this process differs significantly from canonical inflammasome activator ATP-induced vesiculation, and it is dependent on the autocrine IFN signal associated with TLR4 activation. LPS priming preceding the noncanonical inflammasome activation significantly enhances vesicle-mediated secretion of inflammasome components caspase-1, ASC, and lytic cell death effectors GSDMD, MLKL, and NINJ1, suggesting that inflammatory EV transfer may exert paracrine effects in recipient cells. Moreover, using bioinformatics methods, we identify 15-deoxy-Δ12,14-PGJ2 and parthenolide as inhibitors of caspase-4-mediated inflammation and vesicle secretion, indicating new therapeutic potential of these anti-inflammatory drugs.
Keyphrases
- cell death
- inflammatory response
- induced apoptosis
- endothelial cells
- anti inflammatory
- oxidative stress
- cell cycle arrest
- escherichia coli
- toll like receptor
- high throughput
- high glucose
- immune response
- lps induced
- diabetic rats
- amino acid
- induced pluripotent stem cells
- drug delivery
- pluripotent stem cells
- nuclear factor
- signaling pathway
- single cell
- high resolution
- electronic health record
- anti inflammatory drugs
- drug induced
- staphylococcus aureus
- cancer therapy
- pseudomonas aeruginosa
- cystic fibrosis
- multidrug resistant
- candida albicans
- stress induced