Saponins from Panax japonicus attenuate cognitive impairment in ageing rats through regulating microglial polarisation and autophagy.

CONTEXT: Panax japonicus is the dried rhizome of Panax japonicus C.A. Mey. (Araliaceae). Saponins from Panax japonicus (SPJ) exhibit anti-inflammatory and antioxidative effects. OBJECTIVE: To explore the neuroprotective effect of SPJ on natural ageing of rat. MATERIALS AND METHODS: Sprague-Dawley (SD) rats 18-month-old were divided into ageing control, ageing treated with SPJ 10 or 30 mg/kg (n = 8). Five-month-old rats were taken as the adult control (n = 8). Rats were fed regular feed or feed containing SPJ for 4 months. Cognitive level was evaluated by Morris water maze (MWM) test. The mechanisms of SPJ's neuroprotection were evaluated by transmission electron microscope, western blot analysis, and immunofluorescence in vivo and in vitro. RESULTS: SPJ attenuated ageing-induced cognitive impairment as indicated by elevated number of times crossing the target platform (from 1.63 to 3.5) and longer time spent in the target platform quadrant (from 1.33 to 1.98). Meanwhile, SPJ improved the morphology of microglia and synapse, and activated M2 microglia polarisation including increased hippocampus levels of CD206 (from 0.98 to 1.47) and YM-1 (from 0.67 to 1.1), and enhanced autophagy-related proteins LC3B (from 0.48 to 0.82), Beclin1 (from 0.32 to 0.51), Atg5 (from 0.22 to 0.89) whereas decreased p62 level (from 0.71 to 0.45) of ageing rats. In vitro study also showed that SPJ regulated the microglial polarisation and autophagy. DISCUSSION AND CONCLUSIONS: SPJ improved cognitive deficits of ageing rats through attenuating microglial inflammation and enhancing microglial autophagy, which could be used to treat neurodegenerative disorders.

Role of Tumor-Associated Macrophages in Cervical Cancer: Integrating Classical Perspectives with Recent Technological Advances.

Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment, influencing cancer progression and contributing to poor prognosis. However, in cervical cancer (CC), their significance and involvement are relatively less studied than in other gynecological cancers such as ovarian and endometrial cancer. This review aims to provide an overview of TAMs, covering their origins and phenotypes and their impact on CC progression, along with major TAM-targeted therapeutic approaches. Furthermore, we advocate for the integration of cutting-edge research methodologies, such as single-cell RNA sequencing and spatial RNA sequencing, to enable in-depth and comprehensive investigations into TAMs in CC, which would be beneficial in leading to more personalized and effective immunotherapy strategies for patients with CC.

Antagonism of miR-148a attenuates atherosclerosis progression in APOBTGApobec-/-Ldlr+/- mice: A brief report.

OBJECTIVE: miR-148a-3p (miR-148a) is a hepatic and immune-enriched microRNA (miRNA) that regulates macrophage-related lipoprotein metabolism, cholesterol homeostasis, and inflammation. The contribution of miR-148a-3p to the progression of atherosclerosis is unknown. In this study, we determined whether miR-148a silencing mitigated atherogenesis in APOBTGApobec-/-Ldlr+/- mice. METHODS: APOBTGApobec-/-Ldlr+/- mice were fed a typical Western-style diet for 22 weeks and injected with a nontargeting locked nucleic acid (LNA; LNA control) or miR-148a LNA (LNA 148a) for the last 10 weeks. At the end of the treatment, the mice were sacrificed, and circulating lipids, hepatic gene expression, and atherosclerotic lesions were analyzed. RESULTS: Examination of atherosclerotic lesions revealed a significant reduction in plaque size, with marked remodeling of the lesions toward a more stable phenotype. Mechanistically, miR-148a levels influenced macrophage cholesterol efflux and the inflammatory response. Suppression of miR-148a in murine primary macrophages decreased mRNA levels of proinflammatory M1-like markers (Nos2, Il6, Cox2, and Tnf) and increased the expression of anti-inflammatory genes (Arg1, Retlna, and Mrc1). CONCLUSIONS: Therapeutic silencing of miR148a mitigated the progression of atherosclerosis and promoted plaque stability. The antiatherogenic effect of miR-148a antisense therapy is likely mediated by the anti-inflammatory effects observed in macrophages treated with miR-148 LNA and independent of significant changes in circulating low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C).

The roles of macrophage polarization in the host immune response to sepsis.

Sepsis is a life-threatening clinical syndrome caused by infection. Its pathogenesis is complex and entails coagulation dysfunction, inflammation, and immune disorders. Macrophages are important components of innate and adaptive immunity that are highly heterogeneous and plastic. They can polarize into a multi-dimensional spectrum of phenotypes with different functions relating to immune regulation in response to changes in the microenvironment of specific tissues. We reviewed studies that examined the role of macrophage polarization with a focus on the classical activated (M1-like) and alternative activated (M2-like) macrophages as the two main phenotypes involved in the host immune response to sepsis. A complex regulatory network is involved in the process of macrophage polarization, which is influenced by a variety of signaling molecules, transcription factors, epigenetic modifications, and metabolic reprogramming. M1-like macrophages release large quantities of pro-inflammatory mediators, while M2-like macrophages release large quantities of anti-inflammatory mediators. An imbalance between M1-like and M2-like macrophages induces the occurrence and development of sepsis. Therefore, targeted regulation of the process of macrophage polarization could be a useful approach to normalize the immune balance of the host, offering a new treatment modality for different stages of sepsis.

Peritoneal resident macrophages in mice with MLL-AF9-induced acute myeloid leukemia show an M2-like phenotype.

BACKGROUND: Acute myeloid leukemia (AML) is a devastating disease with a poor prognosis. Innate and adaptive immunity is closely related to the progression of leukemia. Macrophages within the leukemic microenvironment have a tendency toward a leukemia-permissive phenotype. However, the characteristics of macrophages in leukemia, including their kinetics, gene expression, and functional roles have not been fully illuminated. METHODS: In the current study, the characteristics of peritoneal resident macrophages, which were large peritoneal macrophages (LPM), from mice with mixed lineage leukemia (MLL)-AF9-induced AML were investigated. AML-associated large macrophages (AML-LPM) were gated as F4/80high MHC-II- by flow cytometry. To further investigate the relationship between the leukemic microenvironment and macrophage characteristics, RNA sequencing was performed. Meanwhile, apoptosis, killing ability, and phagocytic function of peritoneal resident macrophages in MLL-AF9-induced AML were assessed. RESULTS: The results suggested that AML microenvironment was found to affect the kinetics and morphology of peritoneal resident macrophages. The results of RNA sequencing suggested that the gene expression of AML-LPMs differed significantly from that of normal LPMs. The AML microenvironment also had effects on the apoptosis, killing ability, and phagocytic function of peritoneal resident macrophages. CONCLUSIONS: These data suggest that peritoneal resident macrophages in mice with AML induced by MLL-AF9 show an M2-like phenotype. The reversal of macrophage polarization in the leukemic microenvironment may potentially enhance the immunotherapeutic effect in AML.

Differently Charged Super-Paramagnetic Iron Oxide Nanoparticles Preferentially Induced M1-Like Phenotype of Macrophages.

Macrophages are mainly divided into two phenotypes: M1-like (anti-tumoral, pro-inflammatory) and M2-like (pro-tumoral, anti-inflammatory). The more abundant M2-like phenotype of tumor associated macrophages (TAMs) has been associated with poor prognosis in various cancers, therefore, many studies have been carried out to modulate TAMs to change from an M2 to M1-like phenotype as an effective way to suppress tumor growth. Previous study indicated that the FDA-approved Ferumoxytol is an iron oxide nanoparticle that has intrinsic tumor inhibiting properties and is accompanied by the increased presence of the pro-inflammatory, anti-tumoral M1-like phenotype. Intrigued by this finding, we hypothesize that differently charged super-paramagnetic iron oxide nanoparticles (SPIONs) would have preferential differences in polarizing macrophages. Herein, we report that differently charged SPIONs have distinct preferences in the modulation of TAM phenotypes. Positively charged SPION (S+) had the highest cellular uptake and highest macrophage polarization effect. Interestingly, although negatively charged SPION (S-) should present charge-charge repulsion with cell membranes, they showed considerably high uptake in vitro, nevertheless presenting the highest cellular toxicity. Neutrally charged SPION (SN) showed minimal uptake and cellular toxicity in vitro. Both S+ and S- could effectively re-polarize M2-like macrophages toward M1-like macrophages in vitro, and significantly increased the Fenton effect and chemotaxis of macrophages. When macrophages pre-treated with these SPIONs were co-injected with tumor cells to obtain a tumor xenograft, S+ and S- treated macrophages significantly induced tumor retardation, indicating the successful repolarization of tumor macrophages by these SPIONs. Taken together, we provide an insight on the importance of SPION charge in immunomodulation of macrophages.

GBM-Derived Wnt3a Induces M2-Like Phenotype in Microglial Cells Through Wnt/ß-Catenin Signaling.

Glioblastoma is an extremely aggressive and deadly brain tumor known for its striking cellular heterogeneity and capability to communicate with microenvironment components, such as microglia. Microglia-glioblastoma interaction contributes to an increase in tumor invasiveness, and Wnt signaling pathway is one of the main cascades related to tumor progression through changes in cell migration and invasion. However, very little is known about the role of canonical Wnt signaling during microglia-glioblastoma crosstalk. Here, we show for the first time that Wnt3a is one of the factors that regulate interactions between microglia and glioblastoma cells. Wnt3a activates the Wnt/ß-catenin signaling of both glioblastoma and microglial cells. Glioblastoma-conditioned medium not only induces nuclear translocation of microglial ß-catenin but also increases microglia viability and proliferation as well as Wnt3a, cyclin-D1, and c-myc expression. Moreover, glioblastoma-derived Wnt3a increases microglial ARG-1 and STI1 expression, followed by an upregulation of IL-10 mRNA levels, and a decrease in IL1ß gene expression. The presence of Wnt3a in microglia-glioblastoma co-cultures increases the formation of membrane nanotubes accompanied by changes in migration capability. In vivo, tumors formed from Wnt3a-stimulated glioblastoma cells presented greater microglial infiltration and more aggressive characteristics such as growth rate than untreated tumors. Thus, we propose that Wnt3a belongs to the arsenal of factors capable of stimulating the induction of M2-like phenotype on microglial cells, which contributes to the poor prognostic of glioblastoma, reinforcing that Wnt/ß-catenin pathway can be a potential therapeutic target to attenuate glioblastoma progression.

Individual in vivo Profiles of Microglia Polarization After Stroke, Represented by the Genes iNOS and Ym1.

Microglia are the brain-innate immune cells which actively surveil their environment and mediate multiple aspects of neuroinflammation, due to their ability to acquire diverse activation states and phenotypes. Simplified, M1-like microglia are defined as pro-inflammatory cells, while the alternative M2-like cells promote neuroprotection. The modulation of microglia polarization is an appealing neurotherapeutic strategy for stroke and other brain lesions, as well as neurodegenerative diseases. However, the activation profile and change of phenotype during experimental stroke is not well understood. With a combined magnetic resonance imaging (MRI) and optical imaging approach and genetic targeting of two key genes of the M1- and M2-like phenotypes, iNOS and Ym1, we were able to monitor in vivo the dynamic adaption of the microglia phenotype in response to experimental stroke.

Tissue-resident macrophages as replicative niches for intracellular pathogens.

Macrophages are considered a critical component of innate immunity against intracellular pathogens. Although macrophages have historically been viewed as monocyte-derived and terminally differentiated cells, recent progress has revealed that many tissue-resident macrophages are embryonically seeded, self-renewed, and perform homeostatic functions associated with M2-like activation programs. There is evidence that tissue-resident macrophages (TRMs) maintain their M2-like phenotype even in an infection-driven pro-inflammatory environment. In this regard, several intracellular pathogens are shown to exploit M2-like TRMs as replicative niches to evade pathogen-specific immunity. This knowledge provides a new perspective to understand the chronicity of infections and develop therapeutic strategies which can selectively target TRMs.