Biology subjects

Mowel, W. K.

Publications and source records attributed to Mowel, W. K..

3 recordsLinked to original sources

bioRxiv2026

DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity

Over one million patients receive cancer immunotherapy annually, yet the mechanisms underlying life-threatening immune-mediated toxicities remain poorly understood. Checkpoint inhibitor pneumonitis (CIP) is the leading cause of immunotherapy-related mortality, with a case fatality rate approaching 10%, and no genetic risk factors have been described to date. We identified Dipeptidyl-peptidase 9 (DPP9) as the first genetic susceptibility gene for CIP in a clinico-genomics cohort of 4,397 patients treated with immune checkpoint inhibitors. Mechanistically, DPP9 suppresses CARD8 inflammasome activation and IL-18 secretion in human monocytes, a pathway which is engaged prior to CIP onset, with IL-18 selectively elevated in the plasma of patients who subsequently develop CIP. Myeloid-restricted ablation of Dpp8 and Dpp9 in mice recapitulated the pulmonary histopathological and immunological hallmarks of CIP, including granuloma formation, accumulation of IFN{gamma}-producing T cells and monocyte-derived macrophages. Each of these phenotypes were driven by excessive IL-18 secretion. Together, these findings establish DPP9 as a genetic determinant of CIP and nominate IL-18 blockade as a mechanistically rational therapeutic strategy.

immunology↗

bioRxiv2025

FABP5 regulates ether lipid metabolism to ameliorate atopic dermatitis

Atopic dermatitis is an allergic skin disease associated with a profound reorganization of the epidermal lipidome. The effect of the altered lipidome on the skin-resident immune cells that drive disease is unclear. Previous reports identified Fatty acid binding protein 5 (FABP5) as a biomarker for atopic dermatitis, yet how FABP5 might contribute to disease pathogenesis is unknown. Here, we use a murine model of atopic dermatitis, to demonstrate that FABP5 is highly expressed in immune and epithelial cell lineages and that FABP5 protects against skin inflammation. Lipidomic analysis revealed that FABP5 deficiency broadly disrupts the systemic abundance of ether-linked lipids, a minor but important subset of glycerophospholipids. We show that these changes in ether lipid abundance are crucial for the proper regulation of platelet activating factor (PAF), a potent inflammatory ether lipid derivative. Concordantly, we observe elevated PAF in FABP5-deficient mice with dermatitis and that depletion of basophils, a major source of PAF, is sufficient to ameliorate disease in these animals. Altogether, our findings reveal a novel role for FABP5 in the control of allergic inflammation through the modulation of ether lipid and PAF metabolism.

immunology↗

bioRxiv2023

IL-10 constrains sphingolipid metabolism via fatty acid desaturation to limit inflammation

Unchecked chronic inflammation is the underlying cause of many diseases, ranging from inflammatory bowel disease to obesity and neurodegeneration. Given the deleterious nature of unregulated inflammation, it is not surprising that cells have acquired a diverse arsenal of tactics to limit inflammation. IL-10 is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types; however, the exact mechanism by which IL-10 signaling subdues inflammation remains unclear. Here, we find that IL-10 signaling constrains sphingolipid metabolism. Specifically, we find increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10-deficient macrophages. Genetic deletion of CerS2, the enzyme responsible for VLC ceramide production, limited exacerbated inflammatory gene expression associated with IL-10 deficiency both in vitro and in vivo, indicating that "metabolic correction" is able to reduce inflammation in the absence of IL-10. Surprisingly, accumulation of saturated VLC ceramides was regulated by flux through the de novo mono-unsaturated fatty acid (MUFA) synthesis pathway, where addition of exogenous MUFAs could limit both saturated VLC ceramide production and inflammatory gene expression in the absence of IL-10 signaling. Together, these studies mechanistically define how IL-10 signaling manipulates fatty acid metabolism as part of its molecular anti-inflammatory strategy and could lead to novel and inexpensive approaches to regulate aberrant inflammation.

immunology↗