IL-21 collaborates with anti-TIGIT to restore NK cell function in chronic HBV infection.

Available therapies for chronic hepatitis B virus (HBV) infection are not satisfying, and interleukin-21 (IL-21) and checkpoint inhibitors are potential therapeutic options. However, the mechanism underlying IL-21 and checkpoint inhibitors in treating chronic HBV infection is unclear. To explore whether IL-21 and checkpoint inhibitors promote HBV clearance by modulating the function of natural killer (NK) cells, we measured the phenotypes and functions of NK cells in chronic HBV-infected patients and healthy controls on mRNA and protein levels. We found that chronic HBV infection disturbed the transcriptome of NK cells, including decreased expression of KLRK1, TIGIT, GZMA, PRF1, and increased expression of CD69. We also observed altered phenotypes and functions of NK cells in chronic HBV-infected patients, characterized by decreased NKG2D expression, increased TIGIT expression and impaired interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) production. Furthermore, these alterations cannot be restored by telbivudine treatment but can be partially restored by IL-21 and anti-TIGIT stimulation. IL-21 upregulated the expression of activating receptor CD16, CD69, and NKG2D on NK cells, enhanced IFN-γ production, cytolysis, and proliferation of NK cells, while anti-TIGIT promoted IFN-γ production in CD56dim subset exclusively in chronic HBV infected patients. Additionally, IL-21 was indispensable for anti-TIGIT in HBsAg clearance in mice bearing HBV. It enhanced IFN-γ production in splenic NK cells rather than intrahepatic NK cells, indicating a brand-new mechanism of IL-21 in HBV clearance when combined with anti-TIGIT. Overall, our findings contribute to the design of immunotherapy through enhancing the antiviral efficacy of NK cells in chronic HBV infection.

Neuronal C-Reactive Protein/FcγRI Positive Feedback Proinflammatory Signaling Contributes to Nerve Injury Induced Neuropathic Pain.

Neuropathic pain is difficult to treat in clinical practice, and the underlying mechanisms are insufficiently elucidated. Previous studies have demonstrated that the neuronal Fc-gamma-receptor type I (FcγRI) of the dorsal root ganglion (DRG) mediates antigen-specific pain. However, the mechanisms of neuronal FcγRI in neuropathic pain remain to be explored. Here, it is found that the activation of FcγRI-related signals in primary neurons induces neuropathic pain in a rat model. This work first reveals that sciatic nerve injury persistently activates neuronal FcγRI-related signaling in the DRG, and conditional knockout (CKO) of the FcγRI-encoding gene Fcgr1 in rat DRG neurons significantly alleviates neuropathic pain after nerve injury. C-reactive protein (CRP) is increased in the DRG after nerve injury, and CRP protein of the DRG evokes pain by activating neuronal FcγRI-related signals. Furthermore, microinjection of naive IgG into the DRG alleviates neuropathic pain by suppressing the activation of neuronal FcγRI. These results indicate that the activation of neuronal CRP/FcγRI-related signaling plays an important role in the development of neuropathic pain in chronic constriction injury (CCI) rats. The findings may provide novel insights into the neuroimmune responses after peripheral nerve injury and suggest potential therapeutic targets for neuropathic pain.

Bacillus benefits the competitive growth of Ambrosia artemisiifolia by increasing available nutrient levels.

Bacillus can help plants to acquire nutrients either directly or indirectly. However, the role of Bacillus community on the competitive growth of invasive Ambrosia artemisiifolia is poorly understood. Native Setaria viridis is often found in areas that have been invaded by A. artemisiifolia. We sought to determine whether the quantitative and/or qualitative differences in the Bacillus community present on the invasive A. artemisiifolia and native S.viridis provide a competitive advantage to the invasive over native species. A field experiment was established to imitate the invasion of A. artemisiifolia. The 16S rRNA gene was commercially sequenced to identify the bacilli isolated from the rhizosphere soil of field-grown A. artemisiifolia and S. viridis. The Bacillus communities in their rhizosphere were compared, and their effects on the competitive growth of A. artemisiifolia and S. viridis were tested in the pot experiments. Bacillus in the rhizosphere soil of A. artemisiifolia significantly enhanced its intra-specific competitive ability. The relative abundance of B. megaterium in the rhizosphere soil of A. artemisiifolia was significantly higher than that of S. viridis. Inoculation with B. megaterium that was isolated from the rhizosphere soil of both A. artemisiifolia and S. viridis significantly enhanced the relative competitiveness of A. artemisiifolia and inhibited that of S. viridis. The higher abundance of B. megaterium in the rhizosphere of A. artemisiifolia creates higher levels of available nutrients than that in the native S. viridis, which enhance the competitive growth of A. artemisiifolia. The result helps to discover the mechanism of Bacillus community in the invasion of A. artemisiifolia.

Focal-type, but not Diffuse-type, Amyloid Beta Plaques are Correlated with Alzheimer's Neuropathology, Cognitive Dysfunction, and Neuroinflammation in the Human Hippocampus.

Amyloid beta (Aß) plaques are one of the hallmarks of Alzheimer's disease (AD). However, currently available anti-amyloid therapies fail to show effectiveness in the treatment of AD in humans. It has been found that there are different types of Aß plaque (diffuse and focal types) in the postmortem human brain. In this study, we aimed to investigate the correlations among different types of Aß plaque and AD-related neuropathological and cognitive changes based on a postmortem human brain bank in China. The results indicated that focal plaques, but not diffuse plaques, significantly increased with age in the human hippocampus. We also found that the number of focal plaques was positively correlated with the severity of AD-related neuropathological changes (measured by the "ABC" scoring system) and cognitive decline (measured by the Everyday Cognitive Insider Questionnaire). Furthermore, most of the focal plaques were co-localized with neuritic plaques (identified by Bielschowsky silver staining) and accompanied by microglial and other inflammatory cells. Our findings suggest the potential of using focal-type but not general Aß plaques as biomarkers for the neuropathological evaluation of AD.