Biology subjects

Lawlor, K. E.

Publications and source records attributed to Lawlor, K. E..

3 recordsLinked to original sources

bioRxiv2024

A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic condition caused by altered cytokine signaling, maladaptive immunity, dysbiosis, and intestinal barrier dysfunction. Patients with IBD receive therapy to correct these imbalances and achieve remission. However, most patients relapse, suggesting that pathological mechanisms persist during remission. Here, we show that excess epithelial cell death is an underlying feature of IBD that arises in patients in remission and on advanced therapy. Mechanistically, nascent inflammation reprograms epithelial cells into a macrophage-like state that promotes RIPK1-independent necroptotic signaling, then triggers iNOS-mediated mitochondrial apoptosis of absorptive epithelial cells and PUMA-mediated intestinal stem cell death. These findings reveal aberrant epithelial cell death signaling as a hallmark of IBD that occurs early in mucosal lesion development and persists despite current therapeutic approaches. One-Sentence SummaryEpithelial cell death is dysregulated in patients with inflammatory bowel disease.

cell biology↗

bioRxiv2023

Candida auris evades innate immunity by using metabolic strategies to escape and kill macrophages while avoiding antimicrobial inflammation

Candida auris causes life-threatening, drug-resistant infections. In addition to drug resistance, therapeutic innovation is hindered by our limited knowledge of the mechanisms used by C. auris to evade immunity and establish infection. Here we show that C. auris escapes phagocytic containment and kills macrophages, and demonstrate that the mechanisms rely on metabolic regulation. We found that C. auris-infected macrophages undergo immunometabolic reprogramming and increase glycolysis but this does not lead to the expected antimicrobial responses, as macrophages fail to activate IL-1{beta} cytokine and curb C. auris growth. Further analysis showed that C. auris relies on its own metabolic capacity to egress from macrophages, cause macrophage metabolic stress and cell death, and establish infection in vivo. We identified a transcriptional regulator of C. auris metabolism and macrophage evasion, and further show that, contrary to several other pathogens, C. auris-induced macrophage metabolic dysfunction and death fail to activate the NLRP3 inflammasome. Consequently, inflammasome-dependent antimicrobial responses remain inhibited throughout infection. Our findings establish a pivotal role for metabolic regulation in enabling C. auris to eliminate macrophages while remaining immunologically silent to ensure its own survival.

microbiology↗

bioRxiv2021

The inflammasome-activated cytokine IL-1 is targeted for ubiquitylation and proteasomal degradation to limit its inflammatory potential

Interleukin-1{beta} (IL-1{beta}) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in wide-spread diseases. Therefore, IL-1{beta} activity must be fine-tuned to enable antimicrobial responses whilst limiting collateral damage. Here we report that precursor IL-1{beta} is rapidly turned over by the proteasome and this correlates with its decoration by K11-, K63- and K48-linked ubiquitin chains. The ubiquitylation of IL-1{beta} is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1{beta} cleavage by caspase-1. We further demonstrate that IL-1{beta} K133 is modified by ubiquitin and forms a salt bridge with IL-1{beta} D129. Loss of IL-1{beta} K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1{beta}. Accordingly, IL-1{beta}K133R/K133R mice display increased precursor IL-1{beta} upon inflammasome priming and increased bioactive IL-1{beta}, both in vitro and following LPS injection in vivo. These findings reveal new mechanisms for limiting IL-1{beta} activity and safeguarding against damaging inflammation.

immunology↗