Accumulation of amyloid beta peptide (Aβ) in the brain is a pathological hallmark of Alzheimer’s disease (AD); the underlying mechanism, however, is not well understood. In this study, we show that expression of plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), increases with age in the brain of wild type and Aβ precursor protein-presenilin 1 (APP/PS1) transgenic mice as well as in AD patients. Most importantly, we show that knocking out the PAI-1 gene dramatically reduces Aβ burden in the brain of APP/PS1 mice but has no effect on the levels of full-length APP, alpha or beta C-terminal fragments. Furthermore, we show that knocking out the PAI-1 gene leads to increases in the activities of tPA and plasmin, and the plasmin activity inversely correlates with the amounts of SDS insoluble Aβ40 and Aβ42. Together, these data suggest that increased PAI-1 expression/activity contributes importantly to Aβ accumulation during aging and in AD probably by inhibiting plasminogen activation and thus Aβ degradation.

Rationale: Others and we previously discovered in lung myofibroblasts that a metabolic reprogramming into an augmented glycolytic state is critical to their pro-fibrotic phenotype. As the primary glycolysis byproduct, lactate is also secreted into the extracellular milieu, together with which myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a non-cell autonomous effect through the lactate regulation of the pathogenic phenotype of alveolar macrophages. Methods: Bleomycin and TGF-β induced mouse lung fibrosis models were employed. Primary lung alveolar macrophages, bone marrow derived macrophages, and lung fibroblasts were purified and cultured. The effect of lactate on macrophage pro-fibrotic activity was determined by multiple in vitro assays.Results: Here, we demonstrated that there was a markedly increased lactate in the conditioned media of TGF-β1 induced lung myofibroblasts and in the bronchoalveolar lavage fluids (BALFs) from mice with TGF-β1 or bleomycin induced lung fibrosis. Importantly, the media and BALFs promoted pro-fibrotic mediator expression in macrophages. Mechanistically, lactate induced histone lactylation in the promoters of the pro-fibrotic genes in macrophages, consistent with the upregulation of this epigenetic modification in these cells in the fibrotic lungs. The lactate inductions of the histone lactylation and the pro-fibrotic gene expression were mediated by p300, as evidenced by their diminished levels in p300 knockdown macrophages. Conclusions: Collectively, our study establishes for the first time that in addition to protein, lipid, and nucleic acid molecules, a metabolite can also mediate intercellular regulations in the setting of lung fibrosis. Our findings shed new light on the mechanism underlying the key contribution of myofibroblast glycolysis to the pathogenesis of lung fibrosis.

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