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Transcriptomic and ultrastructural evidence indicate that anti-HMGB1 antibodies rescue organic dust-induced
Sanjana Mahadev Bhat1,2,3, Nyzil Massey1, Denusha Shrestha1
1Department of Biomedical Sciences, Iowa State University, Ames, IA, USA.
Abstract:
Exposure to organic dust (OD) in agriculture is known to cause respiratory symptoms including loss of lung function. OD exposure activates multiple signaling pathways since it contains a variety of microbial products and particulate matter. Previously, we have shown how OD exposure leads to the secretion of HMGB1 and HMGB1-RAGE signaling, and how this can be a possible therapeutic target to reduce inflammation. Cellular mitochondria are indispensable for homeostasis and are emerging targets to curtail inflammation. Recently, we have also observed that OD exposure induces mitochondrial dysfunction characterized by loss of structural integrity and deficits in bioenergetics. However, the role of HMGB1 in OD-induced mitochondrial dysfunction in human bronchial epithelial (NHBE) cells remains elusive. Therefore, we aimed to study whether decreased levels of intracellular HMGB1 or antibody-mediated neutralization of secreted HMGB1 would rescue mitochondrial dysfunction. Single and repeated ODE exposure showed an elongated mitochondrial network and cristolysis whereas HMGB1 neutralization or the lack thereof promotes mitochondrial biogenesis evidenced by increased mitochondrial fragmentation, increased DRP1 expression, decreased MFN2 expression, and increased PGC1α expression. Repeated 5-day ODE exposure significantly downregulated transcripts encoding mitochondrial respiration and metabolism (ATP synthase, NADUF, and UQCR) as well as glucose uptake. This was reversed by the antibody-mediated neutralization of HMGB1. Our results support our hypothesis that, in NHBE cells, neutralization of ODE-induced HMGB1 secretion rescues OD-induced mitochondrial dysfunction.
Insights
Neutralizing HMGB1 (High Mobility Group Box 1) secretion rescues mitochondrial dysfunction caused by organic dust exposure in human bronchial cells. This finding offers a potential therapeutic strategy for agricultural respiratory diseases.
Area of Science:
- Respiratory Medicine
- Cellular Biology
- Toxicology
Background:
- Organic dust (OD) exposure in agriculture is linked to respiratory issues and lung function decline.
- OD contains microbial products and particulate matter, activating inflammatory signaling pathways.
- HMGB1 (High Mobility Group Box 1) signaling is implicated in OD-induced inflammation, and mitochondrial dysfunction has been recently observed.
Purpose of the Study:
- To investigate the role of HMGB1 in organic dust-induced mitochondrial dysfunction in normal human bronchial epithelial (NHBE) cells.
- To determine if reducing intracellular HMGB1 or neutralizing secreted HMGB1 can mitigate mitochondrial damage.
Main Methods:
- NHBE cells were exposed to organic dust extract (ODE).
- Mitochondrial morphology and function were assessed.
- HMGB1 neutralization was achieved using antibodies.
- Gene expression related to mitochondrial respiration, metabolism, and biogenesis was analyzed.
Main Results:
- ODE exposure led to mitochondrial elongation and cristolysis.
- HMGB1 neutralization promoted mitochondrial biogenesis, indicated by increased fragmentation, DRP1, and PGC1α expression, and decreased MFN2.
- Repeated ODE exposure downregulated mitochondrial respiration and metabolism genes, which was reversed by HMGB1 neutralization.
Conclusions:
- HMGB1 plays a critical role in mediating organic dust-induced mitochondrial dysfunction in NHBE cells.
- Neutralizing HMGB1 secretion is a promising therapeutic approach to restore mitochondrial homeostasis and function in response to OD exposure.
