Dual-specificity phosphatase 6 (DUSP6) serves a specific and conserved function on the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). We previously identified Dusp6 as a regenerative repressor during zebrafish heart regeneration, therefore we propose to investigate the role of this repressor in mammalian cardiac repair. Utilizing a rat strain harboring Dusp6 nonsense mutation, rat neutrophil-cardiomyocyte co-culture, bone marrow transplanted rats and neutrophil-specific Dusp6 knockout mice, we find that Dusp6 deficiency improves cardiac outcomes by predominantly attenuating neutrophil-mediated myocardial damage in acute inflammatory phase after myocardial infarction. Mechanistically, Dusp6 is transcriptionally activated by p38-C/EBPβ signaling and acts as an effector for maintaining p-p38 activity by down-regulating pERK and p38-targeting phosphatases DUSP1/DUSP16. Our findings provide robust animal models and novel insights for neutrophil-mediated cardiac damage and demonstrate the potential of DUSP6 as a therapeutic target for post-MI cardiac remodeling and other relevant inflammatory diseases.
© 2022. The Author(s).

Guillain-Barré syndrome (GBS), an immune-mediated disorder affecting the peripheral nervous system, is the most common and severe acute paralytic neuropathy. GBS remains to be potentially life-threatening and disabling despite the increasing availability of current standard therapeutic regimens. Therefore, more targeted therapeutics are in urgent need. Macrophages have been implicated in both initiation and resolution of experimental autoimmune neuritis (EAN), the animal model of GBS, but the exact mechanisms remain to be elucidated. It has been increasingly appreciated that exosomes, a type of extracellular vesicles (EVs), are of importance for functions of macrophages. Nevertheless, the roles of macrophage derived exosomes in EAN/GBS remain unclear. Here we determined the effects of macrophage derived exosomes on the development of EAN in Lewis rats. M1 macrophage derived exosomes (M1 exosomes) were found to aggravate EAN via boosting Th1 and Th17 response, while M2 macrophage derived exosomes (M2 exosomes) showed potentials to mitigate disease severity via a mechanism bypassing Th1 and Th17 response. Besides, both M1 and M2 exosomes increased germinal center reactions in EAN. Further in vitro studies confirmed that M1 exosomes could directly promote IFN-γ production in T cells and M2 exosomes were not capable of inhibiting IFN-γ expression. Thus, our data identify a previously undescribed means that M1 macrophages amplify Th1 response via exosomes and provide novel insights into the crosstalk between macrophages and T cells as well.
Copyright © 2020 Du, Yang, Ge, Liu, Zhang, Li, Li, Li, Liu, Dou, Yang and Duan.

Spinal cord injury (SCI) results in perturbations to the immune system leading to increased infection susceptibility. In parallel, the consumption of high-fat diets (HFD) leads to a chronic inflammation in circulation and body tissues. We investigated the impact of 16 weeks of HFD on chronically-injured rats. SCI rats under both chow and HFD showed peripheral leukocyte changes that include reduced percentages of total, helper and cytotoxic T, and natural killer cells. Expression of immune-related genes in the spleen and thymus reflected the impact of both chronic injury and diet. Changes to the immune system following SCI are adversely impacted by HFD consumption.
Copyright © 2020 Elsevier B.V. All rights reserved.

Obesity in women results in reduced fertility and increased complications during pregnancy. Vertical sleeve gastrectomy (VSG) effectively reduces weight, type 2 diabetes, and dyslipidemia, but is also associated with preterm and small-for-gestational age births. The mechanism by which VSG influences fetal development remains unknown. Here we hypothesize that previously reported immune changes during rat VSG pregnancy are reflected long term in the immune system of the offspring. Offspring of VSG and sham dams were evaluated at postnatal day (PND) 21 and PND60. At PND21, VSG pups have lower numbers of circulating B lymphocytes compared with sham pups (P < 0.05) and have lower transcription of lymphocyte marker Ptprc (P < 0.01) in the spleen, while other lymphocyte populations measured are not different. Total plasma IgG is higher (P < 0.01) and C-reactive protein is lower (P < 0.05) in VSG offspring compared with sham offspring at PND21. The central nervous system of VSG pups is also affected at PND21, having higher expression of Il1b mRNA (P < 0.05) and higher immunoreactivity of microglia marker, IBA1, in the hypothalamus. At PND60, the immune-hematological differences are not present; however, mRNA expression of Il1b is elevated (P < 0.001) in the spleen of VSG offspring along with markers of T cells. These data suggest that the immune system of VSG offspring is compromised early in life, but rebounds after weaning and may even become hyperactive. Future work is needed to determine whether the immune system of VSG offspring is capable of mounting a proper defense and whether other aspects of development are affected.