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Prophylactic and therapeutic itaconate treatment alleviates COVID-19-associated lung injury

ABSTRACT:

Although itaconate demonstrates anti-inflammatory and antimicrobial properties as an immunomodulatory metabolite, the therapeutic potential and mechanistic basis of vaccine-induced or prophylactic itaconate administration in COVID-19 intervention remains underexplored. Our studies reveal that intranasal delivery of dNS1-RBD significantly upregulates endogenous itaconate production. Subsequent research reals that both systemic (intraperitoneal) and pulmonary-targeted (intranasal) itaconate administration mitigate acute lung injury by augmenting efferocytosis and reprogramming macrophage lipid metabolism. Metabolomic analyses further uncover that exogenous itaconate modulates amino acid flux, with parallel protection observed through ornithine/arginine supplementation, suggesting a universal metabolic preconditioning mechanism. This conserved tolerance pathway, validated in human BALF scRNA-seq datasets, establishes metabolic intervention as a strategic approach to harmonize antiviral responses and inflammation control during viral challenge.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12827 | MetaboLights | 2025-08-06

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12827_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS12827_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12827_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS12827_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Background: Environmental lipopolysaccharide (LPS) and microbial component-enriched organic dusts cause significant lung diseases. These environmental exposures induce the recruitment and activation of distinct lung monocyte/macrophage subpopulations involved in disease pathogenesis. Given monocyte/macrophage activation is tightly linked to metabolism, the objective of these studies was to determine the role of the immunometabolic regulator, aconitate decarboxylase 1 (ACOD1), in environmental exposure-induced lung inflammation. Methods: Wild-type (WT) mice were intratracheally instilled (I.T.) with 10 ug LPS or saline. Whole lungs were profiled using bulk RNA sequencing or sorted to isolate monocyte/macrophage subpopulations. Sorted subpopulations were then characterized transcriptomically using a NanoString innate immunity multiplex array 48 hours post-exposure. Next, WT and Acod1-/- mice were instilled with LPS, 25% organic dust extract (ODE), or saline with serum, bronchoalveolar lavage fluid (BALF), and lung tissues collected. BALF metabolites of the tricarboxylic acid (TCA) cycle were quantified by mass-spectrometry. Cytokines/chemokines and tissue remodeling mediators were quantitated by ELISA. Lung immune cells were characterized by flow cytometry. Whole body plethysmography was performed 3 hours post-LPS with WT and Acod1-/- mice. Results: By bulk sequencing, Acod1 was one of the most significantly upregulated genes following LPS (vs. saline) exposure of murine whole lungs. Transcriptomic profiling of sorted lung monocyte/macrophage subpopulations corroborated Acod1 significance. Acod1-/- mice treated with LPS (vs. WT) demonstrated decreased BALF levels of itaconate, TCA cycle reprogramming, decreased BALF neutrophils, increased lung CD4+ T cells, decreased BALF and lung levels of TNF-a, and decreased BALF CXCL1. In comparison, Acod1-/- mice treated with ODE (vs. WT) demonstrated decreased serum pentraxin-2, BALF levels of itaconate, lung total cell, neutrophil, monocyte, and B cell infiltrates with decreased BALF levels of TNF-a, IL-6, and decreased lung CXCL1. Mediators of tissue remodeling (TIMP1, MMP8, MMP9) were also decreased in the LPS-exposed Acod1-/- mice, with MMP-9 also decreased in the ODE-exposed Acod1-/- mice. Lung function assessments demonstrated a blunted response to LPS-induced airway hyper-responsiveness in Acod1-/- mice. Conclusion: Acod1 is robustly upregulated in the lungs following LPS-exposure and encodes a key immunometabolic regulator. ACOD1 mediates the pro-inflammatory response to acute inhaled, environmental LPS and organic dust exposure-induced lung inflammation.

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Prophylactic and therapeutic itaconate treatment alleviates COVID-19-associated lung injury

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