Dataset Information

ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1?-dependent manner.

ABSTRACT: Urinary tract infections (UTIs) are frequent, commonly recurrent, and costly. Deficiency in a key autophagy protein, ATG16L1, protects mice from infection with the predominant bacterial cause of UTIs, Uropathogenic E. coli (UPEC). Here, we report that loss of ATG16L1 in macrophages accounts for this protective phenotype. Compared with wild-type macrophages, macrophages deficient in ATG16L1 exhibit increased uptake of UPEC and enhanced secretion of interleukin-1? (IL-1?). The increased IL-1? production is dependent upon activation of the NLRP3 inflammasome and caspase-1. IL-1? secretion was also enhanced during UPEC infection of ATG16L1-deficient mice in vivo, and inhibition of IL-1? signaling abrogates the ATG16L1-dependent protection from UTIs. Our results argue that ATG16L1 normally suppresses a host-protective IL-1? response to UPEC by macrophages.

SUBMITTER: Symington JW

PROVIDER: S-EPMC4532666 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Publications

ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1β-dependent manner.

Symington J W JW Wang C C Twentyman J J Owusu-Boaitey N N Schwendener R R Núñez G G Schilling J D JD Mysorekar I U IU

Mucosal immunology 20150211 6

Urinary tract infections (UTIs) are frequent, commonly recurrent, and costly. Deficiency in a key autophagy protein, ATG16L1, protects mice from infection with the predominant bacterial cause of UTIs, Uropathogenic E. coli (UPEC). Here, we report that loss of ATG16L1 in macrophages accounts for this protective phenotype. Compared with wild-type macrophages, macrophages deficient in ATG16L1 exhibit increased uptake of UPEC and enhanced secretion of interleukin-1β (IL-1β). The increased IL-1β prod ...[more]

PMID: 25669147

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Project description:Inflammation and metabolism are intricately linked during inflammatory diseases in which activation of the nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) inflammasome, an innate immune sensor, is critical. Several factors can activate the NLRP3 inflammasome, but the nature of the link between NLRP3 inflammasome activation and metabolism remains to be thoroughly explored. This study investigates whether the small molecule inhibitor of the NLRP3 inflammasome, MCC950, modulates the lipopolysaccharide (LPS) -and amyloid-β (Aβ)-induced metabolic phenotype and inflammatory signature in macrophages. LPS + Aβ induced IL-1β secretion, while pre-treatment with MCC950 inhibited this. LPS + Aβ also upregulated IL-1β mRNA and supernatant concentrations of TNFα, IL-6 and IL-10, however these changes were insensitive to MCC950, confirming that MCC950 specifically targets inflammasome activation in BMDMs. LPS + Aβ increased glycolysis and the glycolytic enzyme, PFKFB3, and these effects were decreased by MCC950. These findings suggest that NLRP3 inflammasome activation may play a role in modulating glycolysis. To investigate this further, the effect of IL-1β on glycolysis was assessed. IL-1β stimulated glycolysis and PFKFB3, mimicking the effect of LPS + Aβ and adding to the evidence that inflammasome activation impacts on metabolism. This contention was supported by the finding that the LPS + Aβ-induced changes in glycolysis and PFKFB3 were attenuated in BMDMs from NLRP3-deficient and IL-1R1-deficient mice. Consistent with a key role for PFKFB3 is the finding that the PFKFB3 inhibitor, 3PO, attenuated the LPS + Aβ-induced glycolysis. The data demonstrate that activation of the NLRP3 inflammasome, and the subsequent release of IL-1β, play a key role in modulating glycolysis via PFKFB3. Reinstating metabolic homeostasis by targeting the NLRP3 inflammasome-PFKFB3 axis may provide a novel therapeutic target for treatment of acute and chronic disease.

Dataset Information

ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1?-dependent manner.

Publications

ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1β-dependent manner.

Similar Datasets

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