Exosomes derived from vMIP-II-Lamp2b gene-modified M2 cells provide neuroprotection by targeting the injured spinal cord, inhibiting chemokine signals and modulating microglia/macrophage polarization in mice.

Inflammation is one of the key injury factors for spinal cord injury (SCI). Exosomes (Exos) derived from M2 macrophages have been shown to inhibit inflammation and be beneficial in SCI animal models. However, lacking targetability restricts their application prospects. Considering that chemokine receptors increase dramatically after SCI, viral macrophage inflammatory protein II (vMIP-II) is a broad-spectrum chemokine receptor binding peptide, and lysosomal associated membrane protein 2b (Lamp2b) is the key membrane component of Exos, we speculated that vMIP-II-Lamp2b gene-modified M2 macrophage-derived Exos (vMIP-II-Lamp2b-M2-Exo) not only have anti-inflammatory properties, but also can target the injured area by vMIP-II. In this study, using a murine contusive SCI model, we revealed that vMIP-II-Lamp2b-M2-Exo could target the chemokine receptors which highly expressed in the injured spinal cords, inhibit some key chemokine receptor signaling pathways (such as MAPK and Akt), further inhibit proinflammatory factors (such as IL-1ß, IL-6, IL-17, IL-18, TNF-α, and iNOS), and promote anti-inflammatory factors (such as IL-4 and Arg1) productions, and the transformation of microglia/macrophages from M1 into M2. Moreover, the improved histological and functional recoveries were also found. Collectively, our results suggest that vMIP-II-Lamp2b-M2-Exo may provide neuroprotection by targeting the injured spinal cord, inhibiting some chemokine signals, reducing proinflammatory factor production and modulating microglia/macrophage polarization.

The Value of Amide Proton Transfer MRI in the Diagnosis of Malignant and Benign Urinary Bladder Lesions: Comparison With Diffusion-Weighted Imaging.

BACKGROUND: Conventional magnetic resonance imaging (MRI) has certain limitations in distinguishing between malignant and benign urinary bladder (UB) lesions. Amide proton transfer (APT) imaging may provide more diagnostic information than diffusion-weighted imaging (DWI) to distinguish between malignant and benign UB. PURPOSE: To investigate the potential of APT imaging in the diagnosis of malignant and benign UB lesions and to compare its diagnostic efficacy with that of conventional DWI. STUDY TYPE: Prospective. SUBJECTS: Eighty patients with UB lesions. FIELD STRENGTH/SEQUENCE: A 3.0 T/turbo spin echo (TSE) T1-weighted and T2-weighted imaging, single-shot echo planar DWI, and three-dimensional TSE APT imaging. ASSESSMENT: Patients underwent radical cystectomy or transurethral resection of the bladder lesions within 2 weeks after CT urography and MRI examination. APT signal intensity in UB lesions was quantified by the asymmetric magnetization transfer ratio (MTRasym ). MTRasym and apparent diffusion coefficient (ADC) values were measured and compared between malignant and benign UB lesions. STATISTICAL TESTS: Kolmogorov-Smirnov test, Student's t test or Mann-Whitney U test, Spearman rank correlation coefficient, area under the receiver operating characteristic (ROC) curve (AUC), Delong test, and intraclass correlation coefficient (ICC). The significance threshold was set at P < 0.05. RESULTS: Thirty-two patients had pathologically confirmed benign UB lesions, including 2 bladder leiomyomas, 1 submucosal amyloidosis, 1 inflammatory myofibroblastic tumor, and 28 inflammatory lesions, and 48 patients had pathologically confirmed urothelial carcinoma. Urothelial carcinomas showed significantly higher MTRasym values (1.53% [0.74%] vs. 0.85% [0.23%]) and significantly lower ADC values (1.24 ± 0.34 × 10-3 mm2 /s vs. 1.43 ± 0.22 × 10-3 mm2 /s) than benign UB lesions. The MTRasym value (AUC = 0.928) was significantly better in differentiating urothelial carcinoma from benign UB lesions than the ADC value (AUC = 0.722). DATA CONCLUSION: APT imaging may have value in discriminating malignant from benign UB lesions and has better diagnostic performance than DWI. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

The polarization of microglia and infiltrated macrophages in the injured mice spinal cords: a dynamic analysis.

Background: Following spinal cord injury (SCI), a large number of peripheral monocytes infiltrate into the lesion area and differentiate into macrophages (Mø). These monocyte-derived Mø are very difficult to distinguish from the local activated microglia (MG). Therefore, the term Mø/MG are often used to define the infiltrated Mø and/or activated MG. It has been recognized that pro-inflammatory M1-type Mø/MG play "bad" roles in the SCI pathology. Our recent research showed that local M1 cells are mainly CD45-/lowCD68+CD11b+ in the subacute stage of SCI. Thus, we speculated that the M1 cells in injured spinal cords mainly derived from MG rather than infiltrating Mø. So far, their dynamics following SCI are not yet entirely clear. Methods: Female C57BL/6 mice were used to establish SCI model, using an Infinite Horizon impactor with a 1.3 mm diameter rod and a 50 Kdynes force. Sham-operated (sham) mice only underwent laminectomy without contusion. Flow cytometry and immunohistofluorescence were combined to analyze the dynamic changes of polarized Mø and MG in the acute (1 day), subacute (3, 7 and 14 days) and chronic (21 and 28 days) phases of SCI. Results: The total Mø/MG gradually increased and peaked at 7 days post-injury (dpi), and maintained at high levels 14, 21 and 28 dpi. Most of the Mø/MG were activated, and the Mø increased significantly at 1 and 3 dpi. However, with the pathological process, activated MG increased nearly to 90% at 7, 14, 21 and 28 dpi. Both M1 and M2 Mø were increased significantly at 1 and 3 dpi. However, they decreased to very low levels from 7 to 28 dpi. On the contrary, the M2-type MG decreased significantly following SCI and maintained at a low level during the pathological process.

Neuroprotective Effects of the Pannexin-1 Channel Inhibitor: Probenecid on Spinal Cord Injury in Rats.

Proinflammatory immune cell subsets constitute the majority in the local microenvironment after spinal cord injury (SCI), leading to secondary pathological injury. Previous studies have demonstrated that inflammasomes act as an important part of the inflammatory process after SCI. Probenecid, an inhibitor of the Pannexin-1 channel, can inhibit the activation of inflammasomes. This article focuses on the effects of probenecid on the local immune microenvironment, histopathology, and behavior of SCI. Our data show that probenecid inhibited the expression and activation of nucleotide-binding oligomerization domain receptor pyrindomain-containing 1 (NLRP1), apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1, interleukin-1ß (IL-1ß), and caspase-3 proteins associated with inflammasomes, thereby suppressing the proportion of M1 cells. And consequently, probenecid reduced the lesion area and demyelination in SCI. Moreover, the drug increased the survival of motor neurons, which resulted in tissue repair and improved locomotor function in the injured SC. Altogether, existing studies indicated that probenecid can alleviate inflammation by blocking Pannexin-1 channels to inhibit the expression of caspase-1 and IL-1ß, which in turn restores the balance of immune cell subsets and exerts neuroprotective effects in rats with SCI.