High-frequency repetitive transcranial magnetic stimulation improves functional recovery by inhibiting neurotoxic polarization of astrocytes in ischemic rats.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive treatment for ischemic stroke. Astrocytes regulation has been suggested as one mechanism for rTMS effectiveness. But how rTMS regulates astrocytes remains largely undetermined. There were neurotoxic and neuroprotective phenotypes of astrocytes (also denoted as classically and alternatively activated astrocytes or A1 and A2 astrocytes) pertaining to pro- or anti-inflammatory gene expression. Pro-inflammatory or neurotoxic polarized astrocytes were induced during cerebral ischemic stroke. The present study aimed to investigate the effects of rTMS on astrocytic polarization during cerebral ischemic/reperfusion injury. METHODS: Three rTMS protocols were applied to primary astrocytes under normal and oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Cell survival, proliferation, and phenotypic changes were assessed after 2-day treatment. Astrocytes culture medium (ACM) from control, OGD/R, and OGD/R + rTMS groups were mixed with neuronal medium to culture neurons for 48 h and 7 days, in order to explore the influence on neuronal survival and synaptic plasticity. In vivo, rats were subjected to middle cerebral artery occlusion (MCAO), and received posterior orbital intravenous injection of ACM collected from different groups at reperfusion, and at 3 days post reperfusion. The apoptosis in the ischemic penumbra, infarct volumes, and the modified Neurological Severity Score (mNSS) were evaluated at 1 week after reperfusion, and cognitive functions were evaluated using the Morris Water Maze (MWM) tests. Finally, the 10 Hz rTMS was directly applied to MCAO rats to verify the rTMS effects on astrocytic polarization. RESULTS: Among these three frequencies, the 10 Hz protocol exerted the greatest potential to modulate astrocytic polarization after OGD/R injury. Classically activated and A1 markers were significantly inhibited by rTMS treatment. In OGD/R model, the concentration of pro-inflammatory mediator TNF-α decreased from 57.7 to 23.0 Ñ€g/mL, while anti-inflammatory mediator IL-10 increased from 99.0 to 555.1 Ñ€g/mL in the ACM after rTMS treatment. The ACM collected from rTMS-treated astrocytes significantly alleviated neuronal apoptosis induced by OGD/R injury, and promoted neuronal plasticity. In MCAO rat model, the ACM collected from rTMS treatment decreased neuronal apoptosis and infarct volumes, and improved cognitive functions. The neurotoxic astrocytes were simultaneously inhibited after rTMS treatment. CONCLUSION: Inhibition of neurotoxic astrocytic polarization is a potential mechanism for the effectiveness of high-frequency rTMS in cerebral ischemic stroke.

Suppression of the IFN-α and -ß Induction through Sequestering IRF7 into Viral Inclusion Bodies by Nonstructural Protein NSs in Severe Fever with Thrombocytopenia Syndrome Bunyavirus Infection.

Induction of type I IFNs during viral infection is crucial for host defense. IRF 3 and IRF7 play a critical role as key transcription factors in the activation of the IFN induction. Viruses have evolved a variety of strategies to evade innate immunity. Our previous studies have shown that the nonstructural protein (NSs) of the severe fever with thrombocytopenia syndrome virus (SFTSV) can suppress the IFN-ß induction through its interaction with tank-binding kinase-1 and sequestering the inhibitor of nuclear factor kappa B kinase(IKK) complex into the inclusion bodies formed by NSs. In this study, we characterized the unique function of IRF7 in innate immunity and its role in inducing IFN-α in particular, regulated by NSs during the SFTSV infection in several cell types of human origin. Whereas IRF3 is constitutively expressed, IRF7 was significantly induced differentially in various cell types in response to SFTSV infection, promoted the induction of IFN-α2 and -α4, and further induced IFN-ß, thus contributing to suppressing the viral replication. Our data indicate that NSs directly interacted with and sequestered IRF7 into the inclusion bodies, which is different from IRF3 indirectly interacting with NSs. Although interaction of NSs with IRF7 did not inhibit IRF7 phosphorylation, p-IRF7 was trapped in the inclusion bodies, resulting in a significant reduction of the IFN-α2 and -α4 induction and therefore enhanced viral replication. Interaction of the viral NSs with both IRF7 and IRF3 and subsequent sequestration of these transcription factors into viral inclusion bodies, a unique strategy used by this phlebovirus, may ensure effective evasion and suppression of host innate immunity.

Probiotics protect mice from CoCrMo particles-induced osteolysis.

Wear particle-induced inflammatory osteolysis is the primary cause of aseptic loosening, which is the most common reason for total hip arthroplasty (THA) failure in the med- and long term. Recent studies have suggested an important role of gut microbiota (GM) in modulating the host metabolism and immune system, leading to alterations in bone mass. Probiotic bacteria administered in adequate amounts can alter the composition of GM and confer health benefits to the host. Given the inflammatory osteolysis that occurs in wear debris-induced prosthesis loosening, we examined whether the probiotic Lactobacillus casei could reduce osteolysis in a mouse calvarial resorption model. In this study, L. casei markedly protected mice from CoCrMo particles (CoPs)-induced osteolysis. Osteoclast gene markers and the number of osteoclasts were significantly decreased in L. casei-treated mice. Probiotic treatment decreased the M1-like macrophage phenotype indicated by downregulation of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) and increased the M2-like macrophage phenotype indicated by upregulation of IL-4, IL-10 and arginase. Collectively, these results indicated that the L. casei treatment modulated the immune status and suppressed wear particle-induced osteolysis in vivo. Thus, probiotic treatment may represent a potential preventive and therapeutic approach to reduced wear debris-induced osteolysis.