Dataset Information

Comprehensive SWATH-MS-Based Proteomic Analysis of Rat-derived Macrophage Cell Lines Treated with iE-DAP, a NOD1 Agonist

ABSTRACT: Alveolar macrophages play a pivotal role in maintaining pulmonary homeostasis. While their primary function is the phagocytic clearance of xenobiotic substances, our recent studies have demonstrated that they also possess a mechanism for the active uptake of bacterial-derived peptides through peptide transporter 2 (PEPT2). This finding suggests that, in addition to their role in phagocytosis, alveolar macrophages may contribute to inflammatory responses through the PEPT2-dependent internalization of bacterial peptides. In this research project, we aimed to elucidate the mechanisms of inflammation triggered by the bacterial-derived peptide iE-DAP in the absence or presence of PEPT2 inhibitors. To this end, we conducted a comprehensive proteomic analysis of the rat alveolar macrophage cell line NR8383 treated with iE-DAP, employing a highly sensitive and quantitative proteomics technique, SWATH-MS.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Lung, Macrophage

DISEASE(S): Wounds And Injuries

SUBMITTER: Masashi Kawami

LAB HEAD: Yasuo Uchida

PROVIDER: PXD066610 | Pride | 2026-07-04

REPOSITORIES: Pride

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			Action	DRS
	Cont_24hr_250ng_n1.wiff	Wiff
	Cont_24hr_250ng_n1.wiff.scan	Wiff
	Cont_24hr_250ng_n1.wiff2	Wiff
	Cont_24hr_250ng_n1_1.wiff	Wiff
	Cont_24hr_250ng_n1_1.wiff.scan	Wiff

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Project description:Progressive supranuclear palsy (PSP) is a tauopathy that presents region-specific patterns of neurodegeneration, affecting cortical and subcortical areas with relative selectivity. Among these, the anterior cingulate cortex (ACC) is of particular interest due to its involvement in executive functions, which are frequently impaired in PSP. However, the pathophysiological mechanisms underlying such selective vulnerability remain poorly understood. Given the integration of astrocytes into neural circuits, we hypothesized that astrocyte dysfunction and disrupted astrocyte–neuron crosstalk contribute to the metabolic and functional abnormalities observed in the ACC of PSP. To test this hypothesis, we conducted a multimodal analysis integrating SWATH-MS-based proteomics, histopathology, and in vivo magnetic resonance spectroscopy (MRS) in postmortem and living brains of PSP patients and controls. Astrocyte markers GFAP and AQP4 were significantly elevated in PSP-ACC, whereas neuronal markers remained unchanged. AQP4 expression exhibited polarity loss and negatively correlated with neuronal proteins, suggesting glymphatic dysfunction and glial–neuronal uncoupling. Proteomic analysis further revealed upregulation of enzymes related to the IP3–Ca²⁺ signaling cascade and downregulation of calcium extrusion pathways, indicating enhanced astrocytic Ca²⁺ signaling. This was consistent with elevated myo-inositol levels detected by MRS. MRS also revealed significantly increased lactate and glutamate levels in PSP-ACC. Proteomic data showed reduced expression of oxidative phosphorylation–related proteins (e.g., ETFDH, UQCRC1) and pyruvate dehydrogenase components (DLD, PDHX), particularly in astrocytes. These changes correlated with in vivo lactate and myo-inositol concentrations, indicating astrocyte-based metabolic failure. Furthermore, expression of glutamate–glutamine cycle molecules negatively correlated with GFAP and AQP4 levels, suggesting that astrocytic dysfunction underlies impaired excitatory/inhibitory balance. Taken together, these findings demonstrate that multiple aspects of astrocyte–neuron crosstalk—including glymphatic clearance, calcium signaling, mitochondrial metabolism, and neurotransmitter cycling—are selectively impaired in the ACC of PSP. These disruptions likely precede or exacerbate neuronal dysfunction in this region. Our study highlights astrocyte dysfunction as a central feature of PSP pathophysiology and suggests that MRS-detectable metabolites such as myo-inositol and lactate may serve as early, non-invasive biomarkers of glial dysfunction and circuit-level vulnerability in neurodegenerative tauopathies.

Project description:Tan2012 - Antibiotic Treatment, Inoculum Effect The efficacy of many antibiotics decreases with increasing bacterial density, a phenomenon called the ‘inoculum effect’ (IE). This study reveals that, for ribosome-targeting antibiotics, IE is due to bistable inhibition of bacterial growth, which reduces the efficacy of certain treatment frequencies. This model is described in the article: The inoculum effect and band-pass bacterial response to periodic antibiotic treatment. Tan C, Phillip Smith R, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L. Mol Syst Biol. 2012 Oct 9; 8:617 Abstract: The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes. This model is hosted on BioModels Database and identified by: MODEL1208300000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Comprehensive SWATH-MS-Based Proteomic Analysis of Rat-derived Macrophage Cell Lines Treated with iE-DAP, a NOD1 Agonist

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