Biology subjects

West, L. C.

Publications and source records attributed to West, L. C..

3 recordsLinked to original sources

bioRxiv2020

Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune crosstalk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA (mtDNA) instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces healthspan, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increases oxidative stress, enhances pro-inflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyper-inflammatory phenotypes by restoring Nrf2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related diseases and aging.

immunology↗

bioRxiv2020

Innate immune signaling and sex differences contribute to neurocognitive impairment, neuroinflammation, and mitochondrial rewiring in a mouse model of Gulf War illness

Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting approximately 30 percent of the nearly 700,000 veterans of the 1991 Persian Gulf War. Recent studies have revealed that GWI-related chemical (GWIC) exposure promotes immune activation and metabolic rewiring, which correlate with neurocognitive impairments and other symptoms of GWI. However, the molecular mechanisms and signaling pathways linking GWIC to inflammation, metabolic alterations, and neurological symptoms remain unclear. Mitochondrial dysfunction has been documented in veterans with GWI and rodent models, and because mitochondria are key immune regulators, we hypothesized that alterations to mitochondria-immune crosstalk could contribute to the development of GWI-related symptoms. Here we show that acute exposure of murine macrophages to GWIC alters mitochondrial respiration and potentiates innate immune signaling and inflammatory cytokine secretion. Using an established mouse model of GWI, we report that neurobehavioral changes, neuroinflammation, and mitochondrial protein rewiring are attenuated in mice lacking the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) and NOD-, LRR- or pyrin domain-containing protein 3 (NLRP3) innate immune pathways. Finally, we report sex differences in response to GWIC, with female mice showing more pronounced cognitive impairment, neuroinflammation, and mitochondrial protein alterations in the brain compared to male mice. Our results provide novel information on sex differences in this model and suggest that STING and NLRP3 are key mediators of the cognitive impairment, inflammation, and mitochondrial dysfunction observed in GWI.

neuroscience↗

bioRxiv2020

A Versatile Soluble Siglec Scaffold for Sensitive and Quantitative Detection of Glycan Ligands

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are immunomodulatory receptors that are regulated by their glycan ligands. A growing connection between Siglecs and human disease motivates improved methods to detect Siglec ligands. Here, we describe a new versatile set of Siglec-Fc proteins for glycan ligand detection. Enhanced sensitivity and selectivity are enabled through multimerization and avoiding Fc receptors, respectively. Using these Siglec-Fc proteins, Siglec ligands were systemically profiled on healthy and cancerous cells and tissues, revealing many unique patterns. Additional features enable the production of small, homogenous Siglec fragments and development of a quantitative ligand-binding mass spectrometry assay. Using this assay, the ligand specificities of several Siglecs were clarified. For CD33, we demonstrate that it recognizes both 2-3 and 2-6 sialosides in solution and on cells, which has implications for its link to Alzheimers disease susceptibility. These soluble Siglecs reveal the abundance of their glycan ligands on host cells as self-associated molecular patterns.

biochemistry↗