Biology subjects

Sule, G. J.

Publications and source records attributed to Sule, G. J..

3 recordsLinked to original sources

bioRxiv2022

The IRE1α-XBP1 signaling axis promotes glycolytic reprogramming in response to inflammatory stimuli

Immune cells must be able to adjust their metabolic programs to effectively carry out their effector functions. Here, we show that the ER stress sensor IRE1 and its downstream transcription factor XBP1 enhance the upregulation of glycolysis in classically activated macrophages (CAM). The IRE1-XBP1 signaling axis supports this glycolytic switch in macrophages when activated by LPS stimulation or infection with the intracellular bacterial pathogen Brucella abortus. Importantly, these different inflammatory stimuli have distinct mechanisms of IRE1 activation; while TLR4 supports glycolysis under both conditions, TLR4 is required for activation of IRE1 in response to LPS treatment but not B. abortus infection. Though IRE1 and XBP1 are necessary for maximal induction of glycolysis in CAM, activation of this pathway is not sufficient to increase the glycolytic rate of macrophages, indicating that the cellular context in which this pathway is activated ultimately dictates the cells metabolic response and that IRE1 activation may be a way to fine-tune metabolic reprogramming. IMPORTANCEThe immune system must be able to tailor its response to different types of pathogens in order to eliminate them and protect the host. When confronted with bacterial pathogens, macrophages, frontline defenders in the immune system, switch to a glycolysis-driven metabolism to carry out their antibacterial functions. Here, we show that IRE1, a sensor of ER stress, and its downstream transcription factor XBP1 support glycolysis in macrophages during infection with Brucella abortus or challenge with Salmonella LPS. Interestingly, these stimuli activate IRE1 by independent mechanisms. While the IRE1-XBP1 signaling axis promotes the glycolytic switch, activation of this pathway is not sufficient to increase glycolysis in macrophages. This study furthers our understanding of the pathways that drive macrophage immunometabolism and highlights a new role for IRE1 and XBP1 in innate immunity.

immunology↗

bioRxiv2022

Human neutrophils direct epithelial cell extrusion to enhance intestinal epithelial host defense during Salmonella infection

Infection of the human gut by Salmonella enterica Typhimurium (STM) results in a localized inflammatory disease that is not mimicked in murine infections. To determine mechanisms by which neutrophils, as early responders to bacterial challenge, direct inflammatory programming of human intestinal epithelium, we established a multi-component human intestinal organoid (HIO) model of STM infection. HIOs were micro-injected with STM and then seeded with primary human polymorphonuclear leukocytes (PMN-HIOs), specifically neutrophils and analyzed for bacterial growth and host cell survival. Surprisingly, PMNs did not affect luminal colonization of Salmonella, but their presence reduced intraepithelial bacterial burden. Adding PMNs to infected HIOs resulted in substantial accumulation of shed intestinal epithelial cells that could be blocked by Caspase-1 or Caspase-3 inhibition. Cleaved Caspase-3 was present in epithelial cells, but expression of the inflammasome adaptor, ASC, was only detected in PMNs. Caspase inhibition also increased bacterial burden in the epithelium of the PMN-HIO, suggesting PMNs enhance activation of cell death pathways in human intestinal epithelial cells as a protective response to infection. These data support a critical function for neutrophils beyond their antimicrobial role whereby they amplify cell death and extrusion of epithelial cells from the Salmonella-infected intestinal monolayer. Significance statementNeutrophils are early responders to Salmonella intestinal infection, but how they influence infection progression and outcome is unknown. Here we use a co-culture model of human intestinal organoids and human primary neutrophils to study the contribution of human neutrophils to Salmonella infection of the intestinal epithelium. We found that neutrophils markedly enhanced epithelial defenses, including enhancing cell extrusion to reduce intraepithelial burden of Salmonella and association with the epithelium, rather than directly killing Salmonella in the HIO lumen. These findings reveal a novel role for neutrophils in the gut beyond killing invading pathogens and illuminate how neutrophils can reprogram cells in the gut environment to enhance antimicrobial defenses.

microbiology↗

bioRxiv2019

The IRE1α stress signaling axis is a key regulator of neutrophil antimicrobial effector function

Activation of the endoplasmic reticulum stress sensor, IRE1, is required for effective immune responses against bacterial infection and is associated with human inflammatory diseases where neutrophils are a key immune component. However, the specific role of IRE1 in regulating neutrophil effector function has not been studied. Here we show that infection-induced IRE1 activation licenses neutrophil antimicrobial capacity, including IL-1{beta} production, NET formation, and MRSA killing. Inhibition of IRE1 diminished production of mitochondrial reactive oxygen species (mROS) and decreased CASPASE-2 activation, which both contributed to neutrophil antimicrobial activity. Mice deficient in Caspase-2 were highly susceptible to MRSA infection and failed to form NETs in a subcutaneous abscess. IRE1 activation enhanced calcium influx and citrullination of histone H3 (Cit-H3) independently of mROS production, suggesting that IRE1 coordinates multiple pathways required for NET formation. Our data demonstrate that the IRE1-Caspase-2 axis is a major driver of neutrophil activity against MRSA infection and highlight the importance of IRE1 in neutrophil antibacterial function.\n\nOne Sentence SummaryIRE1 controls neutrophil antimicrobial defenses

immunology↗