Biology subjects

Madden, M. Z.

Publications and source records attributed to Madden, M. Z..

7 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↗

bioRxiv2024

Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism

SummaryWe show that the mitochondrial fatty acid synthesis gene Mecr shapes CD4+ T cell metabolism and function. It may be targeted in inflammatory diseases and provides rationale to consider the immunological state of patients with mitochondrial disease. Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid-associated genes essential for T cell subset functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as highly impactful. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Effector and memory T cells were reduced in Mecrfl/fl; Cd4cre mice, and MECR was required for activated CD4+ T cells to efficiently proliferate, differentiate, and survive. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to cell death and sensitivity to ferroptosis. Importantly, Mecr-deficient T cells exhibited fitness disadvantages in inflammatory, tumor, and infection models. mtFAS and MECR thus play important roles in activated T cells and may provide targets to modulate immune functions in inflammatory diseases. The immunological state of MECR- and mtFAS-deficient patients may also be compromised.

immunology↗

bioRxiv2023

HELZ promotes R loop resolution to facilitate DNA double-strand break repair by homologous recombination

R loop homeostasis is critical for DNA double-strand break (DSB) repair; however, how R loops are resolved in this context is poorly understood. Here, we define HELZ as a unique RNA-DNA helicase that resolves R loops to facilitate homologous recombination (HR) repair. From a synthetic lethal etoposide resistance siRNA screen, we found that HELZ depletion causes R loop-mediated hypersensitivity to DSB-inducing agents, and HELZ localizes and binds to DSBs. HELZ preferentially binds to and unwinds RNA-DNA hybrids with 5ssRNA overhangs to promote R loop resolution genome-wide and at DSBs. Interestingly, HELZ facilitates BRCA1 recruitment to DSBs by preventing R loop accumulation, thereby promoting DNA end resection and HR to prevent R loop mediated genomic instability. Our findings define a role for HELZ in resolving R loops critical for HR that promotes genome stability and governs DSB-inducing agent resistance.

molecular biology↗

bioRxiv2023

Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

Females have increased prevalence of many Th17-mediated diseases. While androgen signaling decreases Th17-mediated inflammation, the mechanisms are not fully understood. Th17 cells rely on glutaminolysis; however, it remains unclear whether androgen receptor (AR) signaling in males modifies glutamine metabolism to suppress Th17-mediated inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis. Using allergen-induced airway inflammation models, we determined females, but not males, had a critical reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake by reducing expression of glutamine transporters. These findings were confirmed in circulating human Th17 cells with minimal reliance on glutamine uptake in male compared to female Th17 cells. We found that AR signaling attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for design and implementation of Th17 or glutaminolysis targeted therapeutics. HighlightsO_LIHuman male CD4+ T cells have decreased expression of metabolic enzymes and decreased reliance on glutaminolysis compared to female CD4+ T cells. C_LIO_LIAndrogen signaling decreased mitochondrial metabolism in Th17 cells and decreased airway inflammation. C_LIO_LIAndrogen signaling decreased glutamine uptake and utilization in Th17 cells. C_LI

immunology↗

bioRxiv2022

PD-1 is induced on tumor-associated macrophages in obesity to directly restrain anti-tumor immunity

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can also promote improved survival for some cancers3-5 and enhance responses to some immune checkpoint blockade therapies6-8. The role of the immune system in the obesity-cancer connection and how obesity influences immunotherapy, however, remain unclear. While PD-1 expression by macrophages has been described9-12, we found that obesity selectively induced PD-1 on macrophages and that PD-1 directly impaired macrophage function. Single cell RNA sequencing of murine colorectal carcinoma tumors showed obesity remodeled myeloid and T cell populations, with fewer clonally expanded effector T cells and increased abundance of PD-1+ tumor-associated macrophages (TAM). Cytokines and molecules associated with obesity, including IL-6, leptin, and insulin, and the unsaturated fatty acid palmitate, induced PD-1 expression on macrophages in a glycolysis-dependent manner. PD-1+ TAMs had increased mitochondrial respiration and expression of genes regulating oxidative phosphorylation, lipid uptake and cell cycle while PD-1- TAMs showed greater signatures of phagocytosis and antigen presentation to T cells. These patterns were directly regulated by PD-1, as recombinant PD-L1 reduced macrophage glycolysis and phagocytic capacity, and this was reversed with blocking PD-1 antibody. Conversely, PD-1-deficient Pdcd1-/- TAMs had high rates of glycolysis, phagocytosis, and expression of MHC-II. Myeloid-specific PD-1 deficiency correlated with slower tumor growth, enhanced TAM antigen presentation capability, and increased CD8 T cell activation together with reduced markers of exhaustion. These findings show metabolic signaling in obesity induces PD-1-mediated suppression of TAM function and reveal a unique macrophage-specific mechanism to modulate immune tumor surveillance and checkpoint blockade. This may contribute to increased cancer risk yet improved response to PD-1 blockade in TAM-enriched tumors and obesity.

immunology↗

bioRxiv2020

Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

The tumor microenvironment (TME) includes transformed cancer and infiltrating immune cells1,2. Cancer cells can consume large quantities of glucose through Warburg metabolism3,4 that can be visualized with positron emission tomography (PET). While infiltrating immune cells also rely on glucose, disruptions to metabolism can contribute to tumor immunological evasion5-9. How immune cell metabolism is programmed or restrained by competition with cancer cells for nutrients, remains uncertain. Here we used PET tracers to measure the accessibility of glucose and glutamine to cell subsets in the TME. Surprisingly, myeloid cells including macrophages were the greatest consumers of intra-tumoral glucose, followed by T cells and cancer cells. Cancer cells, in contrast, had the highest glutamine uptake. This distinct nutrient partitioning was programmed through selective mTORC1 signaling and glucose or glutamine-related gene expression. Inhibition of glutamine uptake enhanced glucose uptake across tumor resident cell types and shifted macrophage phenotype, demonstrating glucose is not limiting in the TME. Thus, cancer cells are not the only cells in tumors which exhibit high glucose uptake in vivo and instead preferentially utilize glutamine over other cell types. We observe that intrinsic cellular programs can play a major role in the use of some nutrients. Together, these data argue cell selective partitioning of glucose and glutamine can be exploited to develop therapies and imaging strategies to alter the metabolic programs of specific cell populations in the TME.

cancer biology↗