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Abstract Background The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer. Methods In this study, we constructed novel CAR structures, which consisted of humanized anti-HER2 or CD47 scFv, CD8 hinge region and transmembrane domains, as well as the 4-1BB and CD3ζ intracellular domains. We examined the phagocytosis of HER2 CAR-M and CD47 CAR-M on ovarian cancer cells and the promotion of adaptive immunity. Two syngeneic tumor models were used to estimate the in vivo antitumor activity of HER2 CAR-M and CD47 CAR-M. Results We constructed CAR-Ms targeting HER2 and CD47 and verified their phagocytic ability to ovarian cancer cells in vivo and in vitro. The constructed CAR-Ms showed antigen-specific phagocytosis of ovarian cancer cells in vitro and could activate CD8+ cytotoxic T lymphocyte (CTL) to secrete various anti-tumor factors. For the in vivo model, mice with human-like immune systems were used. We found that CAR-Ms enhanced CD8+ T cell activation, affected tumor-associated macrophage (TAM) phenotype, and led to tumor regression. Conclusions We demonstrated the inhibition effect of our constructed novel HER2 CAR-M and CD47 CAR-M on target antigen-positive ovarian cancer in vitro and in vivo, and preliminarily verified that this inhibitory effect is due to phagocytosis, promotion of adaptive immunity and effect on tumor microenvironment.

Background: Chronic kidney disease (CKD) is now globally recognized as a critical public health concern. Vascular calcification (VC) represents a significant risk factor for cardiovascular events in individuals with CKD. It is the accessible and precise diagnostic biomarkers for monitoring the progression of CKD and the concurrent VC are urgently needed.Methods: The adenine diet-induced CKD rat model was utilized to investigate chronic kidney injury, calcification in the kidney and thoracic aorta, and dysregulation of biochemical indices. Enzyme-linked immune sandwich assays were employed to analyze changes in calcification-related proteins. 16S rRNA sequencing was performed to delineate the microbiota characteristics in the gut and blood of CKD-afflicted rats. Additionally, transcriptome sequencing of kidney tissue was conducted to explore the relationship between CKD-associated microbiota features and alterations in kidney function.Results: The adenine diet-induced CKD inhibited body weight gain, and led to kidney injury, and pronounced calcification in kidney and thoracic aorta. The microbiota both in the gut and blood of these affected rats exhibited significantly lower alpha diversity and distinctive beta diversity than those in their healthy counterparts. CKD resulted in dysregulation of several biochemical indices (including elevated levels of creatinine, low-density lipoprotein-cholesterol, sodium, phosphorous, total cholesterol, and urea and decreased levels of albumin, calcium, lactate dehydrogenase, and total bilirubin). Moreover, it upregulated calcification-related factors (bone sialoprotein [BSP], Klotho, fibroblast growth factor [FGF]-23, and sclerostin [SOST]) and lipopolysaccharide (LPS). Notably, the increased Acinetobacter in the blood was positively associated with calcifications in the kidney and thoracic aorta, in addition to the positive correlation with gut microbiota. The enrichment of Acinetobacter was concurrent with increases in calcification factors (BSP, FGF-23, and SOST), LPS, and phosphorous. Furthermore, transcriptome sequencing revealed that the enrichment of Acinetobacter was positively correlated with the majority of upregulated genes and negatively correlated with downregulated genes involved in the mineral absorption pathway.Conclusion: Our findings, for the first time, underscore that dysbiosis of symbiotic microbiota, both in the gut and blood, is involved in the progression of CKD. Particularly, the enrichment of Acinetobacter in blood emerges as a potential risk factor for CKD and its accompanying VC.

Rheumatoid arthritis (RA) is an inflammation-involved disorder and features the disruption of CD4+ T lymphocytes. Herein, we describe that microRNA-10b-5p (miR-10b) promotes RA progression by disrupting the balance between subsets of CD4+ T cells. MiR-10b-deficient mice protected against collagen antibody-induced arthritis (CAIA) model. RNA sequencing results indicated that disordered genes in miR-10b−/− CAIA model are closely associated with CD4+ T cells differentiation. Moreover, miR-10b mimics promoted Th1/Th17 and suppressed Th2/Treg cells differentiation, whereas miR-10b inhibitor induced contrary effects. In addition, GATA3 and PTEN was confirmed as two targets of miR-10b, and GATA3 siRNA could increase Th1 and reduce Th2 cells meanwhile PTEN siRNA could increase Th17 and decrease Treg cells. Furthermore, miR-10b inhibitor significantly ameliorated collagen-induced arthritis (CIA) development by attenuating the dysfunctional CD4+ T cell subpopulations. The present findings suggest that miR-10b could disrupt the balance of CD4+ T subsets, while suppressed miR-10b could attenuate the severity of experimental arthritis, which provided us a novel mechanistic and therapeutic insight into the RA.

PU.1, a transcription factor member of the E26 transformation-specific family, affects the function of a variety of immune cells in several physiological and pathological conditions. Previous studies studying the role of PU.1 in pathological conditions have mainly focused on immune system-related cancers, and a series of articles have confirmed that PU.1 mutation can induce a variety of immune cell-related malignancies. The underlying mechanism has also been extensively validated. However, the role of PU.1 in other major immune system-related diseases, namely, systemic autoimmune diseases, is still unclear. It was only in recent years that researchers began to gradually realize that PU.1 also played an important role in a variety of autoimmune diseases, such as rheumatoid arthritis (RA), experimental autoimmune encephalomyelitis (EAE) and systemic lupus erythematosus (SLE). This review article summarizes the findings of recent studies that investigated the role of PU.1 in various autoimmune diseases and the related underlying mechanisms. Furthermore, it presents new ideas and provides insight into the role of PU.1 as a potential treatment target for autoimmune diseases and highlights existing research problems and future research directions in related fields.

This study aimed to explore the toxicity of environmental residues of graphene oxide nanoparticles (GONPs) to reproduction of Lepidopteron insects using both ovary cell line (BmN) and individual female Bombyx mori as the research subjects. The results showed that GONPs dose dependently affect BmN cells. At higher concentrations (>25 mg/L), GONPs led to oxidative stress, ROS accumulation and DNA damage in BmN cells and significantly reduced their survival rate (p ≤ 0.05). Moreover, feeding female B. mori larvae with mulberry leaves treated with 25 mg/L GONPs significantly decreased their gonadosomatic index (GSI) by 40.84%, and increased oxidation levels and antioxidant enzyme activity in silkworm ovary tissues. Pathological analysis found that exposure to GONPs decreased the numbers of both oogonia and oocytes in ovarian tissues, increased the formation of peroxisome and vacuoles in follicle cells, reduced the transcription of genes (Vg, Ovo, Sxl-s, Sxl-l, and Otu) related to ovarian development in B. mori by 0.61, 0.65, 0.75, 0.72, and 0.42-fold, respectively, and lowered the amount of spawning by 52.25%. Overall, these results revealed that GONPs exposure is toxic to the reproduction of B. mori. The underlying mechanism is that oxidative stress due to GONPs causes oxidative damage to DNA, damages ovarian tissues, as well as hinders B. mori development and spawning. Thus, this study provides important experimental data for safety evaluation of reproductive toxicity due to GONPs exposure.

The ontogeny of macrophages in most organs has already been established. Owing to the limited number and inaccessibility of synovial macrophages (SMs), the origin of SMs has not been fully elucidated. Previous studies suggested that SMs have two major origins, namely, tissue-resident and monocyte-derived SMs. However, no systematic analysis to identify SM ontology in either physiological or pathological conditions has been available to date. In this review, we summarize relevant studies on the two main origins of SMs in rheumatoid arthritis (RA) and forecast the future research directions for this field. Furthermore, we discuss the current state of RA therapy that is based on targeting different SM subsets.

The ontogeny of macrophages in most organ/tissues in human body has been proven. Due to the limited number and inaccessibility of synovial macrophages (SM), the origin of SM has not been fully illuminated. The objective of this study was designed to investigate the ontogeny of SM and to evaluate the role of SM from different origins in arthritis. Two origins of SM, embryonic SM (ESM) and bone marrow SM (BMSM) were identified in Cx3cr1-EGFP mice, CCR2−/− mice and bone marrow (BM) chimera model by using a stringent sorting strategy. The cellular features, including dynamic total cell number, in situ proliferation, phagocytosis and expressions of pro-inflammatory and anti-inflammatory genes, of ESM and BMSM were compared. In addition, ESM and BMSM showed different expression patterns in Rheumatoid Arthritis (RA) patients' synovium and during the developmental process of collagen-induced arthritis (CIA) mice. Taken together, these results demonstrated that the SM at least has two origins, ESM and BMSM. The different cellular property and dynamic expression patterns in RA patients/CIA mice highlight the notion that ESM and BMSM might play different role in arthritis.

The plant extract “total glucosides of peony” (TGP) constitutes a mixture of glycosides that is isolated from the roots of the well-known traditional Chinese herb Paeonia lactiflora Pall. Paeoniflorin (Pae) is the most abundant component and the main biologically active ingredient of TGP. Pharmacologically, Pae exhibits powerful anti-inflammatory and immune regulatory effects in some animal models of autoimmune diseases including Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). Recently, we modified Pae with an addition of benzene sulfonate to achieve better bioavailability and higher anti-inflammatory immune regulatory effects. This review summarizes the pharmacological activities of Pae and the novel anti-inflammatory and immunomodulatory agent Paeoniflorin-6′-O-benzenesulfonate (CP-25) in various chronic inflammatory and autoimmune disorders. The regulatory effects of Pae and CP-25 make them promising agents for other related diseases, which require extensive investigation in the future.