Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis.

Osteoarthritis (OA) is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA. These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium. In this study, we found that phosphoglycerate mutase 5 (PGAM5) significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models. To address the role of PGAM5 in macrophages in OA, we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo. Mechanistically, we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways, whereas inhibited M2 polarization via STAT6-PPARγ pathway in murine bone marrow-derived macrophages. Furthermore, we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2 (DVL2) which resulted in the inhibition of ß-catenin and repolarization of M2 macrophages into M1 macrophages. Conditional knockout of both PGAM5 and ß-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice. Motivated by these findings, we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection, which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis. Collectively, these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.

GSDMD suppresses keratinocyte differentiation by inhibiting FLG expression and attenuating KCTD6-mediated HDAC1 degradation in atopic dermatitis.

Background: Recent studies have shown that activated pyroptosis in atopic dermatitis (AD) switches inflammatory processes and causes abnormal cornification and epidermal barrier dysfunction. Little research has focused on the interaction mechanism between pyroptosis-related genes and human keratinocyte differentiation. Methods: The AD dataset from the Gene Expression Omnibus (GEO) was used to identify differently expressed pyroptosis-related genes (DEPRGs). Hub genes were identified and an enrichment analysis was performed to select epithelial development-related genes. Lesions of AD patients were detected via immunohistochemistry (IHC) to verify the hub gene. Human keratinocytes cell lines, gasdermin D (GSDMD) overexpression, Caspase1 siRNA, Histone Deacetylase1 (HDAC1) siRNA, and HDAC1 overexpression vectors were used for gain-and-loss-of-function experiments. Regulation of cornification protein was determined by qPCR, western blot (WB), immunofluorescence (IF), dual-luciferase reporter assay, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP). Results: A total of 27 DEPRGs were identified between either atopic dermatitis non-lesional skin (ANL) and healthy control (HC) or atopic dermatitis lesional skin (AL) and HC. The enrichment analysis showed that these DEPRGs were primarily enriched in the inflammatory response and keratinocytes differentiation. Of the 10 hub genes identified via the protein-protein interaction network, only GSDMD was statistically and negatively associated with the expression of epithelial tight junction core genes. Furthermore, GSDMD was upregulated in AD lesions and inhibited human keratinocyte differentiation by reducing filaggrin (FLG) expression. Mechanistically, GSDMD activated by Caspase1 reduced FLG expression via HDAC1. HDAC1 decreased FLG expression by reducing histone acetylation at the FLG promoter. In addition, GSDMD blocked the interaction of Potassium Channel Tetramerization Domain Containing 6 (KCTD6) and HDAC1 to prohibit HDAC1 degradation. Conclusion: This study revealed that GSDMD was upregulated in AD lesions and that GSDMD regulated keratinocytes via epigenetic modification, which might provide potential therapeutic targets for AD.

Controls of Mineral Solubility on Adsorption-Induced Molecular Fractionation of Dissolved Organic Matter Revealed by 21 T FT-ICR MS.

Mineral adsorption-induced molecular fractionation of dissolved organic matter (DOM) affects the composition of both DOM and OM adsorbed and thus stabilized by minerals. However, it remains unclear what mineral properties control the magnitude of DOM fractionation. Using a combined technique approach that leverages the molecular composition identified by ultrahigh resolution 21 T Fourier transform ion cyclotron resonance mass spectrometry and adsorption isotherms, we catalogue the compositional differences that occur at the molecular level that results in fractionation due to adsorption of Suwannee River fulvic acid on aluminum (Al) and iron (Fe) oxides and a phyllosilicate (allophane) species of contrasting properties. The minerals of high solubility (i.e., amorphous Al oxide, boehmite, and allophane) exhibited much stronger DOM fractionation capabilities than the minerals of low solubility (i.e., gibbsite and Fe oxides). Specifically, the former released Al3+ to solution (0.05-0.35 mM) that formed complexes with OM and likely reduced the surface hydrophobicity of the mineral-OM assemblage, thus increasing the preference for adsorbing polar DOM molecules. The impacts of mineral solubility are exacerbated by the fact that interactions with DOM also enhance metal release from minerals. For sparsely soluble minerals, the mineral surface hydrophobicity, instead of solubility, appeared to be the primary control of their DOM fractionation power. Other chemical properties seemed less directly relevant than surface hydrophobicity and solubility in fractionating DOM.

Biomimetic triphasic silk fibroin scaffolds seeded with tendon-derived stem cells for tendon-bone junction regeneration.

The regeneration of tendon and bone junctions (TBJs), a fibrocartilage transition zone between tendons and bones, is a challenge due to the special triphasic structure. In our study, a silk fibroin (SF)-based triphasic scaffold consisting of aligned type I collagen (Col I), transforming growth factor ß (TGF-ß), and hydroxyapatite (HA) was fabricated to mimic the compositional gradient feature of the native tendon-bone architecture. Rat tendon-derived stem cells (rTDSCs) were loaded on the triphasic SF scaffold, and the high cell viability suggested that the scaffold presents good biocompatibility. Meanwhile, increased expressions of tenogenic-, chondrogenic-, and osteogenic-related genes in the TBJs were observed. The in vivo studies of the rTDSC-seeded scaffold in a rat TBJ rupture model showed tendon tissue regeneration with a clear transition zone within 8 weeks of implantation. These results indicated that the biomimetic triphasic SF scaffolds seeded with rTDSCs have great potential to be applied in TBJ regeneration.

Culprit Plaques of Large Parent Arteries, Rather than Cerebral Small Vessel Disease, Contribute to Early Neurological Deterioration in Stroke Patients with Intracranial Branch Atheromatous Disease.

INTRODUCTION: Intracranial branch atheromatous disease (BAD) has been applied to occlusions that occur at the origin of large caliber penetrating arteries due to the microatheromas or large parent artery plaques. This study aimed to explore the association between culprit plaques of large parent arteries, neuroimaging markers of cerebral small vessel disease (CSVD), and the risk of early neurological deterioration (END) in stroke patients with BAD. METHODS: A total of 97 stroke patients with BAD in the vascular territories of the lenticulostriate arteries or paramedian pontine arteries, diagnosed using high-resolution magnetic resonance imaging, were prospectively recruited in this observational study. A culprit plaque in the middle cerebral artery was defined as the only arterial plaque on the ipsilateral side of an infarction visible on diffusion-weighted imaging. A culprit plaque in the basilar artery (BA) was identified when it was observed within the same axial slices of an infarction or on the adjacent upper or lower slice, whereas a plaque within the BA located in the ventral region was considered non-culprit. If more than one plaque was present in the same vascular territory, the most stenotic plaque was chosen for the analysis. Four CSVD neuroimaging markers, including white matter hyperintensity, lacunes, microbleeds, and enlarged perivascular spaces, were evaluated in accordance with the total CSVD score. The associations between neuroimaging features of lesions within large parent arteries, neuroimaging markers of CSVD, and the risk of END in stroke patients with BAD were investigated using logistic regression analysis. RESULTS: END occurred in 41 stroke patients (42.27%) with BAD. The degree of large parent artery stenosis (p < 0.001), culprit plaques of large parent arteries (p < 0.001), and plaque burden (p < 0.001) were significantly different between the END and non-END groups in stroke patients with BAD. In logistic regression analysis, culprit plaques of large parent arteries (odds ratio, 32.258; 95% confidence interval, 4.140-251.346) were independently associated with the risk of END in stroke patients with BAD. CONCLUSIONS: Culprit plaques of large parent arteries could predict the risk of END in stroke patients with BAD. These results suggest that lesions in the large parent arteries, rather than damage to the cerebral small vessels, contribute to END in stroke patients with BAD.

Composite Classical Hodgkin Lymphoma and Mantle Cell Lymphoma: A Case Report.

Composite lymphoma implies the presence of two or more morphological and immunophenotypical subtypes of lymphoma in a single tissue or organ. Composite lymphoma with concurrent mantle cell lymphoma (MCL) and classical Hodgkin lymphoma is extremely rare. In this case report, we present the case of a 70-year-old male who was diagnosed with a composite of MCL and classical Hodgkin lymphoma (cHL) and achieved near-complete resolution with chemoimmunotherapy. To the best of our knowledge, this is the first case of this kind demonstrating the effectiveness of a combination chemoimmunotherapy regimen leading to complete remission in composite lymphoma involving MCL and cHL. We report the history, imaging findings, and pathology and illustrate the challenges in therapeutic decision-making in managing composite lymphoma patients involving MCL and cHL. We also review the literature on this rare entity and discuss its clinical implications.

MiR146a modulates chondrogenesis of bone marrow mesenchymal stem cells by modulating Lsm11 expression.

MicroRNAs play a critical role in bone marrow mesenchymal stem cell (MSC) chondrogenesis and regulate the progression of joint regeneration in osteoarthritis. Our previous research confirmed that miR146a relieves osteoarthritis by modulating cartilage homeostasis. However, few studies have revealed the relationship between miR146a and the chondrogenesis of MSCs, and the exact mechanisms remain unclear. This study aimed to determine the function of miR146a in the chondrogenic differentiation of MSCs and the potential mechanisms involved. MiR146a expression increased during chondrogenesis. MiR146a knockout (KO) led to the increased chondrogenesis of MSCs compared to that in wild-type (WT) MSCs, whereas the overexpression of miR146a by mimics resulted in the decreased chondrogenesis of MSCs, as determined by the mRNA expression of collagen, type II, alpha 1 (COL2A1), aggrecan, cartilage oligomeric matrix protein (COMP), and matrix metallopeptidase 13 (MMP13). Furthermore, cartilage defects could be treated better when injected with spheres induced from miR146aKO MSCs than from WT MSCs, indicating that miR146a inhibits chondrogenesis in vivo. In addition, based on miRNA-mRNA prediction analysis and a dual-luciferase reporter assay, we observed that the deletion of miR146a led to the increased expression of Lsm11 during chondrogenesis and demonstrated that miR146a targeted Lsm11 by binding to its 3'-untranslated region (UTR) and inhibited its translation. The inhibition of Lsm11 by silencing RNA (siRNA) reversed the increased ability of chondrogenesis by knocking out miR146a both in vivo and in vitro, suggesting that miR146a inhibits chondrogenesis by directly inhibiting Lsm11 in MSCs, which may be a novel target for treating osteoarthritis.

Nano-calcium silicate mineralized fish scale scaffolds for enhancing tendon-bone healing.

Tendon-bone healing is essential for an effective rotator cuff tendon repair surgery, however, this remains a significant challenge due to the lack of biomaterials with high strength and bioactivity. Inspired by the high-performance exoskeleton of natural organisms, we set out to apply natural fish scale (FS) modified by calcium silicate nanoparticles (CS NPs) as a new biomaterial (CS-FS) to overcome the challenge. Benefit from its "Bouligand" microstructure, such FS-based scaffold maintained excellent tensile strength (125.05 MPa) and toughness (14.16 MJ/m3), which are 1.93 and 2.72 times that of natural tendon respectively, allowing it to well meet the requirements for rotator cuff tendon repair. Additionally, CS-FS showed diverse bioactivities by stimulating the differentiation and phenotypic maintenance of multiple types of cells participated into the composition of tendon-bone junction, (e.g. bone marrow mesenchymal stem cells (BMSCs), chondrocyte, and tendon stem/progenitor cells (TSPCs)). In both rat and rabbit rotator cuff tear (RCT) models, CS-FS played a key role in the tendon-bone interface regeneration and biomechanical function, which may be achieved by activating BMP-2/Smad/Runx2 pathway in BMSCs. Therefore, natural fish scale -based biomaterials are the promising candidate for clinical tendon repair due to their outstanding strength and bioactivity.

3D printing of gear-inspired biomaterials: Immunomodulation and bone regeneration.

It is of significance to construct the immunomodulatory and osteogenic microenvironment for three dimension (3D) regeneration of bone tissues. 3D scaffolds, with various chemical composition, macroporous structure and surface characteristics offer a beneficial microenvironment for bone tissue regeneration. However, there is a gap between the well-ordered surface microstructure of bioceramic scaffolds and immune microenvironment for bone regeneration. In this study, a gear-inspired 3D scaffold with well-ordered surface microstructure was successfully prepared through a modified extrusion-based 3D printing strategy for immunomodulation and bone regeneration. The prepared gear-inspired scaffolds could induce M2 phenotype polarization of macrophages and further promoted osteogenic differentiation of bone mesenchymal stem cells in vitro. The subsequent in vivo study demonstrated that the gear-inspired scaffolds were able to attenuate inflammation and further promote new bone formation. The study develops a facile strategy to construct well-ordered surface microstructure which plays a key role in 3D immunomodulatory and osteogenic microenvironment for bone tissue engineering and regenerative medicine. STATEMENT OF SIGNIFICANCE.

Inhibition of interaction between ROCK1 and Rubicon restores autophagy in endothelial cells and attenuates brain injury after prolonged ischemia.

Acute ischemic stroke (AIS) induces cerebral endothelial cell death resulting in the breakdown of the blood-brain barrier (BBB). Endothelial cell autophagy acts as a protective mechanism against cell death. Autophagy is activated in the very early stages of ischemic stroke and declines after prolonged ischemia. Previous studies have shown that Rubicon can inhibit autophagy. The current study aimed to investigate whether continuous long-term ischemia can inhibit autophagy in endothelial cells after ischemic stroke by regulating the function of Rubicon and its underlying mechanism. Wild-type male C57BL/6J mice were subjected to transient middle cerebral artery occlusion (tMCAO). ROCK1, ROCK2, and NOX2 inhibitors were injected into male mice 1 h before the onset of tMCAO. Disease severity and BBB permeability were evaluated. bEnd.3 cells were cultured in vitro and subjected to oxygen-glucose deprivation (OGD). bEnd.3 cells were pretreated with or without ROCK1, ROCK2, or NOX2 inhibitors overnight and then subjected to OGD. Cell viability and permeability were also evaluated. The expression of Rubicon, ROCK1, and autophagy-related proteins were analyzed. Increased BBB permeability was correlated with Rubicon expression in tMCAO mice and Rubicon was upregulated in endothelial cells subjected to OGD. Autophagy was inhibited in endothelial cells after long-term OGD treatment and knockdown of Rubicon expression restored autophagy and viability in endothelial cells subjected to 6-h OGD. ROCK1 inhibition decreased the interaction between Beclin1 and Rubicon and restored cell viability and autophagy suppressed by 6-h OGD treatment in endothelial cells. Additionally, ROCK1 inhibition suppressed Rubicon, attenuated BBB disruption, and brain injury induced by prolonged ischemia in 6-h tMCAO mice. Prolonged ischemia induced the death of brain endothelial cells and the breakdown of the BBB, thus aggravating brain injury by increasing the interaction of ROCK1 and Rubicon with Beclin1 while inhibiting canonical autophagy. Inhibition of ROCK1 signaling in endothelial cells could be a promising therapeutic strategy to prolong the therapeutic time window in AIS.

Disease Course and Outcomes in Patients With the Limited Form of Neuromyelitis Optica Spectrum Disorders and Negative AQP4-IgG Serology at Disease Onset: A Prospective Cohort Study.

BACKGROUND AND PURPOSE: Patients presenting with clinical characteristics that are strongly suggestive of neuromyelitis optica spectrum disorders (NMOSD) have a high risk of developing definite NMOSD in the future. Little is known about the clinical course, treatment, and prognosis of these patients with likely NMOSD at disease onset. METHODS: This study prospectively recruited and visited 24 patients with the limited form of NMOSD (LF-NMOSD) at disease onset from November 2012 to June 2021. Their demographics, clinical course, longitudinal aquaporin-4 immunoglobulin G (AQP4-IgG) serology, MRI, therapeutic management, and outcome data were collected and analyzed. RESULTS: The onset age of the cohort was 38.1±12.0 years (mean±standard deviation). The median disease duration was 73.5 months (interquartile range=44.3-117.0 months), and the follow-up period was 54.2±23.8 months. At the end of the last visit, the final diagnosis was categorized into AQP4-IgG-seronegative NMOSD (n=16, 66.7%), AQP4-IgG-seropositive NMOSD (n=7, 29.2%), or multiple sclerosis (n=1, 4.2%). Seven of the 24 patients (29.2%) experienced conversion to AQP4-IgG seropositivity, and the interval from onset to this serological conversion was 37.9±21.9 months. Isolated/mixed area postrema syndrome (APS) was the predominant onset phenotype (37.5%). The patients with isolated/mixed APS onset showed a predilection for conversion to AQP4-IgG seropositivity. All patients experienced a multiphasic disease course, with immunosuppressive therapy reducing the incidence rates of clinical relapse and residual functional disability. CONCLUSIONS: Definite NMOSD may be preceded by LF-NMOSD, particularly isolated/mixed APS. Intensive long-term follow-up and attack-prevention immunotherapeutic management is recommended in patients with LF-NMOSD.

Immunosuppressant and neuromyelitis optica spectrum disorder: optimal treatment duration and risk of discontinuation.

BACKGROUND AND PURPOSE: Preventing relapse by immunosuppressants (ISs) is critical for the prognosis of neuromyelitis optica spectrum disorder (NMOSD); however, the optimal duration of IS treatment is still under discussion. The objective was to explore the optimal duration of IS treatment and the risk of IS discontinuation for NMOSD. METHOD: This cohort study was conducted at a major neurological center that housed the largest NMOSD database in South China. Eligible participants were patients with NMOSD undergoing IS treatment. The main outcome measures were changes in relapse risk based on IS treatment duration, clinical outcomes and predictors of relapse following IS discontinuation. RESULTS: In total, 343 patients were included in this study. The duration of IS treatment was strongly associated with a decrease in relapse risk (hazard ratio [HR] 0.53, p < 0.001). Continuous IS treatment resulted in decreased relapse HRs within 5 years of receiving IS medication, with a mild rebound starting at 5 years. Rituximab reduced the risk of NMOSD relapse to approximately zero within 3 years. The rate of relapse after IS withdrawal was high (77.5%). As opposed to other ISs, a delayed relapse following rituximab withdrawal was observed in this study. Longitudinal extensive transverse myelitis (HR = 2.023, p = 0.006) was associated with a higher risk of relapse after IS discontinuation. CONCLUSIONS: Long-term IS medication for NMOSD is generally suitable. Patients with longitudinal extensive transverse myelitis had a higher risk of relapse after IS discontinuation. Future studies should explore individualized strategies of rituximab maintenance treatment.

Cells-Micropatterning Biomaterials for Immune Activation and Bone Regeneration.

Natural tissues are composed of ordered architectural organizations of multiple tissue cells. The spatial distribution of cells is crucial for directing cellular behavior and maintaining tissue homeostasis and function. Herein, an artificial bone bioceramic scaffold with star-, Tai Chi-, or interlacing-shaped multicellular patterns is constructed. The "cross-talk" between mesenchymal stem cells (MSCs) and macrophages can be effectively manipulated by altering the spatial distribution of two kinds of cells in the scaffolds, thus achieving controllable modulation of the scaffold-mediated osteo-immune responses. Compared with other multicellular patterns, the Tai Chi pattern with a 2:1 ratio of MSCs to macrophages is more effective in activating anti-inflammatory M2 macrophages, improving MSCs osteogenic differentiation, and accelerating new bone formation in vivo. In brief, the Tai Chi pattern generates a more favorable osteo-immune environment for bone regeneration, exhibiting enhanced immunomodulation and osteogenesis, which may be associated with the activation of BMP-Smad, Oncostatin M (OSM), and Wnt/ß-catenin signaling pathways in MSCs mediated by macrophage-derived paracrine signaling mediators. The study suggests that the manipulation of cell distribution to improve tissue formation is a feasible approach that can offer new insights for the design of tissue-engineered bone substitutes with multicellular interactions.

Microbially Catalyzed Biomaterials for Bone Regeneration.

Bone is a complex mineralized tissue composed of various organic (proteins, cells) and inorganic (hydroxyapatite, calcium carbonate) substances with micro/nanoscale structures. To improve interfacial bioactivity of bone-implanted biomaterials, extensive efforts are being made to fabricate favorable biointerface via surface modification. Inspired by microbially catalyzed mineralization, a novel concept to biologically synthesize the micro/nanostructures on bioceramics, microbial-assisted catalysis, is presented. It involves three processes: bacterial adhesion on biomaterials, production of CO3 2- assisted by bacteria, and nucleation and growth of CaCO3 nanocrystals on the surface of bioceramics. The microbially catalyzed biominerals exhibit relatively uniform micro/nanostructures on the surface of both 2D and 3D α-CaSiO3 bioceramics. The topographic and chemical cues of the grown micro/nanostructures present excellent in vitro and in vivo bone-forming bioactivity. The underlying mechanism is closely related to the activation of multiple biological processes associated with bone regeneration. The study offers a microbially catalytic concept and strategy of fabricating micro/nanostructured biomaterials for tissue regeneration.

Successful treatment with immunoadsorption therapy in four patients with severe and refractory anti-N-methyl-D-aspartate receptor encephalitis.

There is still no optimal treatment for patients with severe anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis refractory to first-line therapy (including intravenous methylprednisolone [IVMP] and intravenous immunoglobulin [IVIG]). A small study has shown that immunoadsorption (IA) is effective in treating anti-NMDAR encephalitis. However, the effectiveness and safety of IA in the treatment of patients with refractory and severe anti-NMDAR encephalitis is not fully known. Four patients with severe anti-NMDAR encephalitis are reported, which were refractory to the first-line immunotherapy including IVMP and IVIG. Immunoadsorption is performed during the fulminant stage of disease, and the effectiveness and safety of IA are assessed. The modified Rankin Scale (mRS) is used to assess neurological conditions before and after IA. Four patients with the most severe form of anti-NMDAR encephalitis (two with teratoma and two with unknown origin) did not respond to one or more rounds of IVMP plus IVIG. They all required intensive care unit (ICU) support including long-term mechanical ventilation, and thus developed ICU-related complications. Gradual and steady improvement was observed after IA treatment. Except for mild hypotension in patient 1, no other adverse events were observed during IA. Two patients had good early overall recovery on discharge. The other two patients had a good outcome with mRS of 2 at the 12-month follow-up. This small case series suggests that IA may be an effective treatment option to accelerate the recovery of patients with severe and refractory anti-NMDAR encephalitis.

Protein A immunoadsorption for the treatment of refractory anti-N-methyl-d-aspartate receptor encephalitis: A single-center prospective study.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of protein A immunoadsorption (IA) for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis resistant to intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIG). METHODS: We prospectively evaluated patients with refractory anti-NMDAR encephalitis, treated with protein A IA. Demographic data, clinical characteristics, modified Rankin Score (mRS), and anti-NMDAR antibodies were documented before and after IA and at follow-up. Clinical improvement was defined as a decrease of mRS ≥1. Adverse events were recorded throughout the study. RESULTS: Ten patients with mRS ≥3 were enrolled and treated with protein A IA; treatment was performed for an average of 5.2 times per patient. Among the nine patients with positive serum anti-NMDAR, the titer decreased in seven patients, of which two became negative. The cerebrospinal fluid (CSF) anti-NMDAR titer decreased in all patients, and one became negative. Anti-NMDAR levels were tested in two patients at follow-up and found to have declined continuously. All patients exhibited clinical improvement with a mRS decline ≥1 after IA treatment (median mRS: 5.0 [range, 3.0-5.0] vs. 4.0 [range, 2.0-4.0], p = 0.014), and the median mRS decreased to 1.0 (range, 0-3.0) at follow-up. After IA, all patients exhibited accelerated recovery. No adverse events were observed during IA treatment. CONCLUSION: Protein A IA may be effective for treating IVMP/IVIG-resistant anti-NMDAR encephalitis and well tolerated. It is necessary to initiate larger-scale prospective controlled studies to validate the efficacy and safety of protein A IA in anti-NMDAR encephalitis.

Bridging Therapy for Acute Stroke as the Initial Manifestation of Takayasu Arteritis: A Case Report and Review of Literature.

Takayasu arteritis (TA) is a chronic inflammatory disease involving the aorta and its principal branches. Acute ischaemic stroke (AIS) as the initial manifestation of TA is uncommon. There is little evidence on the efficacy of bridging therapy for AIS induced by TA. A 23-year-old Chinese woman with a suspected stroke presented to our hospital with sudden onset of right-sided weakness, right facial palsy, and aphasia that occurred 1 hour ago. After physical and ancillary examinations, recombinant tissue plasminogen activator was administered to the patient, which led to partial recovery. Her neurological function deteriorated with a large salvageable ischaemic penumbra on computed tomography perfusion. Cerebrovascular angiography showed multiple stenoses in the brachiocephalic trunk, the beginning of the right common carotid artery (CCA), and the bilateral subclavian arteries, as well as occlusion of the left CCA and its branches. Mechanical thrombectomy of the left middle cerebral artery was performed immediately. Percutaneous transluminal balloon angioplasty of the left CCA followed by stent implantation of the proximal left CCA was then performed. A diagnosis of TA was made based on the findings. The patient's neurological deficit fully recovered with immunosuppressants at the 3 month-follow-up. We report a rare case of a patient with TA initially presenting with AIS treated with bridging therapy with full recovery of neurological function. Bridging therapy should be taken into consideration for AIS in patients with TA. Further study is needed in this regard.

Temporal and Spatial Dynamics of Inflammasome Activation After Ischemic Stroke.

Background: The inflammasome represents a highly pro-inflammatory mechanism. It has been identified that inflammasome was activated after ischemic stroke. However, the impact of inflammasomes on stroke outcomes remains contradictory. The participating molecules and the functioning arena of post-stroke inflammasome activation are still elusive. Methods: In the present study, blood samples from stroke patients were collected and analyzed with flow cytometry to evaluate the correlation of inflammasome activation and stroke outcomes. A stroke model was established using male C57/Bl6 mice with transient middle cerebral artery occlusion (tMCAO, 1 h). The dynamics of inflammasome components, cell type, and location of inflammasome activation and the therapeutic effects of inhibiting post-stroke inflammasome executors were evaluated. Results: We found that a high level of inflammasome activation might indicate detrimental stroke outcomes in patients and mice models. Post-stroke inflammasome activation, especially NLRP3, cleaved Caspase-1, cleaved Caspase-11, IL-1ß, IL-18, and GSDMD, peaked at 3-5 days and declined at 7 days with the participation of multiple components in mice. Macrophage that infiltrated into the ischemic lesion was the main arena for post-stroke inflammasome activation among myeloid cells according to the data of mice. Among all the members of the Caspase family, Caspase-1 and -11 served as the main executing enzymes. Inhibiting Caspase-1/-11 signaling efficiently suppressed DAMPs-induced macrophage inflammasome activation and displayed neuroprotection to stroke models including infarct size (Control: 48.05 ± 14.98; Cas1.i: 19.34 ± 12.21; Cas11.i: 21.43 ± 14.67, P < 0.001) and neurological deficit score (0 d-Control: 2.20 ± 0.63; 0 d-Cas1.i: 2.20 ± 0.63; 0 d-Cas11.i: 2.20 ± 0.63; 1 d-Control: 2.50 ± 0.53; 1 d-Cas1.i: 1.50 ± 0.71; 1 d-Cas11.i: 2.00 ± 0.67; 2 d-Control: 2.30 ± 0.48; 2 d-Cas1.i: 1.30 ± 0.48; 2 d-Cas11.i: 1.50 ± 0.53; 3 d-Control: 2.00 ± 0.67; 3 d-Cas1.i: 1.20 ± 0.42; 3 d-Cas11.i: 1.30 ± 0.48, P < 0.001). Conclusions: Taken together, inflammasome activation played a detrimental role in stroke pathology. Targeting post-stroke inflammasome executing enzymes fitting in the dynamics of macrophages might obtain potential and efficient therapeutic effects.

High-salt diet downregulates TREM2 expression and blunts efferocytosis of macrophages after acute ischemic stroke.

BACKGROUND: A high-salt diet (HSD) is one of the major risk factors for acute ischemic stroke (AIS). As a potential mechanism, surplus salt intake primes macrophages towards a proinflammatory phenotype. In this study, whether HSD could blunt the efferocytic capability of macrophages after ischemic stroke, thus exacerbating post-stroke neural inflammation, was investigated. METHODS: Wild-type male C57BL/6 mice were fed with fodder containing 8% sodium chloride for 4 weeks and subjected to transient middle cerebral occlusion (tMCAO). Disease severity, macrophage polarization as well as efferocytic capability were evaluated. Bone marrow-derived macrophages were cultured in vitro, and the impact of high salinity on their efferocytic activity, as well as their expression of phagocytic molecules, were analyzed. The relationships among sodium concentration, macrophage phenotype, and disease severity in AIS patients were explored. RESULTS: HSD-fed mice displayed increased infarct volume and aggravated neurological deficiency. Mice fed with HSD suffered exacerbated neural inflammation as shown by higher inflammatory mediator expression and immune cell infiltration levels. Infiltrated macrophages within stroke lesions in HSD-fed mice exhibited a shift towards proinflammatory phenotype and impaired efferocytic capability. As assessed with a PCR array, the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a receptor relevant to phagocytosis, was downregulated in high-salt-treated bone marrow-derived macrophages. Enhancement of TREM2 signaling restored the efferocytic capacity and cellular inflammation resolution of macrophages in a high salinity environment in vitro and in vivo. A high concentration of urine sodium in AIS patients was found to be correlated with lower TREM2 expression and detrimental stroke outcomes. CONCLUSIONS: HSD inhibited the efferocytic capacity of macrophages by downregulating TREM2 expression, thus impeding inflammation resolution after ischemic stroke. Enhancing TREM2 signaling in monocytes/macrophages could be a promising therapeutic strategy to enhance efferocytosis and promote post-stroke inflammation resolution.

Case Report: Central Nervous System Immune Reconstitution Inflammatory Syndrome Related to Bacterial Meningitis.

Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) describes clinical characteristics that may be observed in previously immunocompromised patients during rapid restoration of immunity function in the presence of a pathogen. There have been no reports about CNS-IRIS related to bacterial meningitis so far. Here, we report a 24-year-old pregnant female patient with bacterial meningitis. Her clinical and neuroradiological condition worsened after induced labor despite great effective anti-infective therapy. CNS-IRIS was considered. Corticosteroids were administered, and the patient gradually recovered. We present the first case of CNS-IRIS associated with bacterial meningitis.