Hepatocyte mitochondrial DNA mediates macrophage immune response in liver injury induced by trichloroethylene.

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism of polarization is unclear. Recent studies have shown that TLR9 activation plays an important regulatory role in macrophage polarization. In the present study, we demonstrated that elevated levels of oxidative stress in hepatocytes mediate the release of mtDNA into the bloodstream, leading to the activation of TLR9 in macrophages to regulate macrophage polarization. In vivo experiments revealed that pretreatment with SS-31, a mitochondria-targeting antioxidant peptide, reduced the level of oxidative stress in hepatocytes, leading to a decrease in mtDNA release. Importantly, SS-31 pretreatment inhibited TLR9 activation in macrophages, suggesting that hepatocyte mtDNA may activate TLR9 in macrophages. Further studies revealed that pharmacological inhibition of TLR9 by ODN2088 partially blocked macrophage activation, suggesting that the level of macrophage activation is dependent on TLR9 activation. In vitro experiments involving the extraction of mtDNA from TCE-sensitized mice treated with RAW264.7 cells further confirmed that hepatocyte mtDNA can activate TLR9 in mouse peritoneal macrophages, leading to macrophage polarization. In summary, our study comprehensively confirmed that TLR9 activation in macrophages is dependent on mtDNA released by elevated levels of oxidative stress in hepatocytes and that TLR9 activation in macrophages plays a key role in regulating macrophage polarization. These findings reveal the mechanism of macrophage activation in TCE-induced immune liver injury and provide new perspectives and therapeutic targets for the treatment of OMDT-induced immune liver injury.

The optimal extent of lymph node dissection in N1b papillary thyroid microcarcinoma based on clinicopathological factors and preoperative ultrasonography.

Background: The optimal extent of lymph node (LN) dissection in the management of N1b papillary thyroid microcarcinoma (PTMC) is still under debate in clinical practice, so we aimed to identify the risk factors associated with multilevel lateral lymph node metastasis (LLNM) with regard to the extent of LN dissection. Methods: The clinical data of 182 N1b PTMC patients between January 2019 and June 2021 at Tianjin Medical University Cancer Institute and Hospital were retrospectively reviewed. The frequency pattern and distribution of LLNM were analyzed for risk factors. We assessed the diagnostic value of preoperative ultrasonography (USG) for identifying levels II-V metastasis in PTMC patients. Results: The proportion of multilevel LLNM in N1b PTMC was 72.1%, and the most common pattern was metastasis at two levels (41.2%). Capsule invasion [odds ratio (OR) =6.861, 95% confidence interval (CI): 1.462-32.190, P=0.015], upper pole [OR =2.125, 95% CI: 1.010-4.473, P=0.047], central LN ratio [OR =7.315, 95% CI: 1.309-40.877, P=0.023], thyroid-stimulating hormone (TSH) >1.5 mIU/mL [OR =2.773, 95% CI: 1.269-6.060, P=0.011], and extranodal extension (ENE) [OR =2.632, 95% CI: 1.207-5.739, P=0.015] were independent risk factors for multilevel metastasis. In addition, unltrasonography had high sensitivity and specificity in the diagnosis of metastasis at level V (75.0%, 78.4%) and multilevel LLNM (67.2%, 64.8%). Conclusions: Modified radical neck dissection (MRND) in N1b PTMC patients may be reserved for patients with simultaneous 3-level LLNM or clinically evident metastasis at level V. Preoperative USG may have certain suggestive significance in the diagnosis of multilevel LLNM in primary PTMC.