ABSTRACT
Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.
Subject(s)
Glycolysis , Hypoxia-Inducible Factor 1, alpha Subunit , Interleukin-17 , Animals , Humans , Interleukin-17/metabolism , Interleukin-17/immunology , Mice , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Skin/immunology , Skin/pathology , Skin/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Glucose Transporter Type 1/metabolism , Glucose Transporter Type 1/genetics , Psoriasis/immunology , Psoriasis/metabolism , Epithelium/immunology , Epithelium/metabolism , Mice, Knockout , Signal Transduction/immunology , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Disease Models, Animal , Lactic Acid/metabolism , Chronic Disease , Inflammation/immunology , Mice, Inbred C57BLABSTRACT
In motile cilia, a mechanoregulatory network is responsible for converting the action of thousands of dynein motors bound to doublet microtubules into a single propulsive waveform. Here, we use two complementary cryo-EM strategies to determine structures of the major mechanoregulators that bind ciliary doublet microtubules in Chlamydomonas reinhardtii. We determine structures of isolated radial spoke RS1 and the microtubule-bound RS1, RS2 and the nexin-dynein regulatory complex (N-DRC). From these structures, we identify and build atomic models for 30 proteins, including 23 radial-spoke subunits. We reveal how mechanoregulatory complexes dock to doublet microtubules with regular 96-nm periodicity and communicate with one another. Additionally, we observe a direct and dynamically coupled association between RS2 and the dynein motor inner dynein arm subform c (IDAc), providing a molecular basis for the control of motor activity by mechanical signals. These structures advance our understanding of the role of mechanoregulation in defining the ciliary waveform.
