(R324) Depletion of Lysozyme M+ Cells Offers Cardiovascular, but not Cerebral, Protection from Noise-Induced Stress

Katie Frenis (University Medical Center of Johannes Gutenberg University)| Johanna Helmstädter (University Medical Center of Johannes Gutenberg University)| Sanela Kalinovic (University Medical Center of Johannes Gutenberg University)| Yue Ruan (University Medical Center of Johannes Gutenberg University)| Swenja Kröller-Schön (University Medical Center of Johannes Gutenberg University)| Maria Teresa Bayo Jimenez (University Medical Center of Johannes Gutenberg University)| Matthias Oelze (University Medical Center of Johannes Gutenberg University)| Clemens Sommer (German Center for Cardiovascular Research (DZHK))| Katrin Frauenknecht (German Center for Cardiovascular Research (DZHK))| Adrian Gericke (University Medical Center of Johannes Gutenberg University)| Andreas Daiber (University Medical Center of Johannes Gutenberg University, German Center for Cardiovascular Research (DZHK))| Thomas Münzel (University Medical Center of Johannes Gutenberg University, German Center for Cardiovascular Research (DZHK))| Sebastian Steven (University Medical Center of Johannes Gutenberg University, University Medical Center of Johannes Gutenberg University, University Medical Center of Johannes Gutenberg University)

Background and Hypothesis: Increased leukocyte extravasation in the aortic endothelium leads to a pro-oxidant and pro-inflammatory environment which facilitates the development of endothelial dysfunction. Moderate hypertension, endothelial dysfunction, and increases in oxidative stress are associated with exposure to the novel cardiovascular risk, noise pollution. Since we have previously established a role for myelomonocytes (LysM+ cells) in the deleterious effects of noise exposure, we hypothesized that partial ablation of these cells would protect from cardiovascular consequences.

Methods: LysM+ immune cells were depleted with diphtheria toxin (DTX) in LysMCre+/-iDTR+/- mice for 6 days prior to noise exposure (mean SPL; 72 dBA) and 4 days concurrently. Blood pressure was determined by tail cuff method. Endothelial dysfunction was measured with isometric tension recordings. Protein and gene analysis were carried out using Western Blot, dot blot, and rtPCR. Oxidative stress measurements included dihydroethidium HPLC and staining. Inflammatory cell infiltration was assessed via FACS. Astrocyte and microglia activation were measured by GFAP+ and Iba1+ staining.

Results: Ablation of LysM+ cells successfully normalized the blood pressure as well as aortic and retinal vessel endothelial function of mice exposed to 4 days of noise. Noise caused a significant increase in superoxide production in aortic and cardiac tissue. Mice with ablated LysM+ cells were protected from increased oxidative stress and its effects. The DTX +Noise group was protected from expression of inflammatory genes in aortic tissue. These effects were not seen in brain or cortical tissue, where microglia and astrocyte activation were increased and there was a general failure of protection from noise in inflammatory gene (NFκB2, CD40L, TNFα) and protein (CD68, LysM, CD40, IL6) expression. Noise, DTX, and DTX +Noise groups were all found to have heightened levels of stress hormones in plasma.

Conclusion: Ablation of myelomonocytic cells was successful in rescuing mice from the cardiovascular damage associated with noise exposure, suggesting that these cells play a critical role in the damage incurred upon noise exposure. However, this protection was only found in the vasculature and a distinctly different outcome was discovered in the brain, where a neuroinflammatory phenotype persisted. Heightened levels of hormones indicate that the stress response following noise exposure remains intact in the brain following immune ablation, but is not carried forth to the vasculature, both implicating LysM+ cells in the oxidative damage caused by noise exposure and also in playing an important role the hormone signaling resultant from stress reactions.



Ablation of LysM+ cells protected mice from the detrimental effects of noise exposure in the heart, micro- and macrovasculature, but not in the brain. Made with BioRender.com