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Abstract
The inflammasome-associated proteins caspase-1, caspase-4 and NLRP3 have been emphasised to be essential in the host cell response during urinary tract infection (UTI) by regulating IL-1β release. Our aim was to investigate how the inflammasome-associated proteins regulate the cell response of bladder epithelial cells during infection with uropathogenic Escherichia coli (UPEC). Human bladder epithelial cells (5637) and CRISPR/Cas9 generated caspase-1, caspase-4 and NLRP3 knockdown cells were stimulated with the UPEC strain CFT073. Using Olink proteomics and real time RT-PCR, we showed that caspase-1, caspase-4 and NLRP3 are vital for the expression of many inflammatory genes and proteins from bladder epithelial cells. When investigating the effect of inflammasome-associated proteins on neutrophils, we found that conditioned medium from UPEC-infected caspase-4 knockdown cells significantly increased phagocytosis of CFT073 and significantly decreased ROS production from neutrophils. In contrast, conditioned medium from UPEC-infected NLRP3 knockdown cells significantly decreased the phagocytosis of CFT073 and significantly increased the ROS production from neutrophils. In conclusion, we showed that the inflammasome-associated proteins contribute to the host cell response during UPEC infection.
Highlights
The inflammasome-associated proteins caspase-1, caspase-4 and NACHT leucin-rich repeat PYD protein 3 (NLRP3) have been emphasised to be essential in the host cell response during urinary tract infection (UTI) by regulating IL-1β release
These results show that caspase-1, caspase-4 and NLRP3 are involved in IL-1β and lactate dehydrogenase (LDH) release from bladder epithelial cells
In this study we showed that the release of IL-1β and LDH was significantly reduced in caspase-1, caspase-4 and NLRP3-knockdown cells compared to CFT073 stimulated Cas[9] cells
Summary
The inflammasome-associated proteins caspase-1, caspase-4 and NLRP3 have been emphasised to be essential in the host cell response during urinary tract infection (UTI) by regulating IL-1β release. Our aim was to investigate how the inflammasome-associated proteins regulate the cell response of bladder epithelial cells during infection with uropathogenic Escherichia coli (UPEC). To successfully colonize bladder epithelial cells, UPEC have developed a wide range of mechanisms to avoid the innate immune system They can suppress epithelial cytokine production by controlling NF-κB activity by genes involved in LPS biosynthesis or in α-hemolysin (HlyA)-dependent w ay[4]. There is at present limited knowledge regarding the contribution of caspase-1, caspase-4 and NLRP3 in the release of other inflammatory mediators from the bladder epithelial cells upon a UPEC infection. The aim of this study was to investigate how the inflammasome-associated proteins caspase-1, caspase-4 and NLRP3 regulate the cell response of bladder epithelial cells during UPEC infection
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