Ferroptosis contribute to neonicotinoid imidacloprid-evoked pyroptosis by activating the HMGB1-RAGE/TLR4-NF-κB signaling pathway

Dongfang Zhang; Chunling Wu; Deyan Ba; Nan Wang; Yanling Wang; Xinlian Li; Qiuyue Li; Guifang Zhao

doi:10.1016/j.ecoenv.2023.114655

Ferroptosis contribute to neonicotinoid imidacloprid-evoked pyroptosis by activating the HMGB1-RAGE/TLR4-NF-κB signaling pathway

Ecotoxicol Environ Saf. 2023 Mar 15:253:114655. doi: 10.1016/j.ecoenv.2023.114655. Epub 2023 Feb 20.

Authors

Dongfang Zhang¹, Chunling Wu², Deyan Ba³, Nan Wang¹, Yanling Wang², Xinlian Li², Qiuyue Li², Guifang Zhao⁴

Affiliations

¹ Department of Pathology, Jilin Medical University, Jilin 130013, Jilin Province, PR China.
² Department of Pathphysiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China.
³ The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, Guangdong Province, PR China.
⁴ Department of Pathology, Jilin Medical University, Jilin 130013, Jilin Province, PR China. Electronic address: Zhaogf11@mails.jlu.edu.cn.

PMID: 36812867
DOI: 10.1016/j.ecoenv.2023.114655

Abstract

Imidacloprid (IMI) is among the common neonicotinoid insecticides used in agriculture worldwide, posing a potential toxic threat to non-target animals and humans. Numerous studies have shown that ferroptosis is involved in the pathophysiological progression of renal diseases. However, it remains unclear whether ferroptosis is involved in IMI-induced nephrotoxicity. In the present study, we investigated the potential pathogenic role of ferroptosis in IMI-induced kidney damage in vivo. Transmission electron microscopy (TEM) showed that the mitochondrial crest of kidney cells significantly decreased following IMI exposure. Moreover, IMI exposure triggered ferroptosis and lipid peroxidation in the kidney. We confirmed that nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant capability was negatively correlated with the ferroptosis induced by IMI exposure. Importantly, we verified that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)-driven inflammation occurred in the kidneys following IMI exposure, but pretreatment with the ferroptosis inhibitor ferrostatin (Fer-1) blocked this phenomenon. Additionally, IMI exposure induced F4/80⁺ macrophages to accumulated in the proximal tubules of the kidneys, and also increased the protein expression of high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), receptor for advanced glycation end products (TLR4), and nuclear factor kappa-B (NF-κB). In contrast, inhibition of ferroptosis by Fer-1 blocked IMI-induced NLRP3 inflammasome activation, F4/80 positive macrophages, and the HMGB1-RAGE/TLR4 signaling pathway. To the best of our knowledge, this is the first study to reveal that IMI stress can induce Nrf2 inactivation, thereby triggering ferroptosis, causing an initial wave of death, and activating HMGB1-RAGE/TLR4 signaling, which promotes pyroptosis that perpetuates kidney dysfunction.

Keywords: Ferroptosis; High-mobility group box 1 (HMGB1); Imidacloprid (IMI); Nephrotoxicity; Pyroptosis.

MeSH terms

Animals
Ferroptosis*
HMGB1 Protein* / metabolism
Humans
NF-E2-Related Factor 2 / metabolism
NF-kappa B / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Neonicotinoids / toxicity
Pyroptosis
Receptor for Advanced Glycation End Products / metabolism
Signal Transduction
Toll-Like Receptor 4 / metabolism

Substances

NF-kappa B
Receptor for Advanced Glycation End Products
imidacloprid
Toll-Like Receptor 4
NLR Family, Pyrin Domain-Containing 3 Protein
HMGB1 Protein
NF-E2-Related Factor 2
Neonicotinoids
TLR4 protein, human