» Articles » PMID: 36928191

Impaired PPARγ Activation by Cadmium Exacerbates Infection-induced Lung Injury

Overview
Journal JCI Insight
Date 2023 Mar 17
PMID 36928191
Authors
Affiliations
Soon will be listed here.
Abstract

Emerging data indicate an association between environmental heavy metal exposure and lung disease, including lower respiratory tract infections (LRTIs). Here, we show by single-cell RNA sequencing an increase in Pparg gene expression in lung macrophages from mice exposed to cadmium and/or infected with Streptococcus pneumoniae. However, the heavy metal cadmium or infection mediated an inhibitory posttranslational modification of peroxisome proliferator-activated receptor γ (PPARγ) to exacerbate LRTIs. Cadmium and infection increased ERK activation to regulate PPARγ degradation in monocyte-derived macrophages. Mice harboring a conditional deletion of Pparg in monocyte-derived macrophages had more severe S. pneumoniae infection after cadmium exposure, showed greater lung injury, and had increased mortality. Inhibition of ERK activation with BVD-523 protected mice from lung injury after cadmium exposure or infection. Moreover, individuals residing in areas of high air cadmium levels had increased cadmium concentration in their bronchoalveolar lavage (BAL) fluid, increased barrier dysfunction, and showed PPARγ inhibition that was mediated, at least in part, by ERK activation in isolated BAL cells. These observations suggest that impaired activation of PPARγ in monocyte-derived macrophages exacerbates lung injury and the severity of LRTIs.

Citing Articles

Involvement of ERK and Oxidative Stress in Airway Exposure to Cadmium Chloride Aggravates Airway Inflammation in Ovalbumin-Induced Asthmatic Mice.

Wu C, Hu X, Jiang Y, Tang J, Ge H, Deng S Toxics. 2024; 12(4).

PMID: 38668459 PMC: 11054730. DOI: 10.3390/toxics12040235.


The Correlation between Metal Mixed Exposure and Lung Function in Different Ages of the Population.

Chen Z, Gu H, Zhou R, Cheng S Metabolites. 2024; 14(3).

PMID: 38535299 PMC: 10972184. DOI: 10.3390/metabo14030139.


Urinary cadmium concentration is associated with the severity and clinical outcomes of COVID-19: a bicenter observational cohort study.

Chiu L, Lee C, Hsu P, Li H, Chan T, Hsiao C Environ Health. 2024; 23(1):29.

PMID: 38504259 PMC: 10949676. DOI: 10.1186/s12940-024-01070-6.


Environmental Cadmium Exposure Perturbs Gut Microbial Dysbiosis in Ducks.

Wang X, Mi J, Yang K, Wang L Vet Sci. 2023; 10(11).

PMID: 37999472 PMC: 10674682. DOI: 10.3390/vetsci10110649.

References
1.
Zhu L, Yang T, Li L, Sun L, Hou Y, Hu X . TSC1 controls macrophage polarization to prevent inflammatory disease. Nat Commun. 2014; 5:4696. DOI: 10.1038/ncomms5696. View

2.
Ward-Kavanagh L, Lin W, Sedy J, Ware C . The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity. 2016; 44(5):1005-19. PMC: 4882112. DOI: 10.1016/j.immuni.2016.04.019. View

3.
Xavier M, Winter M, Spees A, den Hartigh A, Nguyen K, Roux C . PPARγ-mediated increase in glucose availability sustains chronic Brucella abortus infection in alternatively activated macrophages. Cell Host Microbe. 2013; 14(2):159-70. PMC: 3777723. DOI: 10.1016/j.chom.2013.07.009. View

4.
Ahmad F, Anderson R . The Leading Causes of Death in the US for 2020. JAMA. 2021; 325(18):1829-1830. PMC: 8145781. DOI: 10.1001/jama.2021.5469. View

5.
Knapp S, Leemans J, Florquin S, Branger J, Maris N, Pater J . Alveolar macrophages have a protective antiinflammatory role during murine pneumococcal pneumonia. Am J Respir Crit Care Med. 2002; 167(2):171-9. DOI: 10.1164/rccm.200207-698OC. View