Cardiac resident macrophages: Spatiotemporal distribution, development, physiological functions, and their translational potential on cardiac diseases.

Cardiac resident macrophages (CRMs) are the main population of cardiac immune cells. The role of these cells in regeneration, functional remodeling, and repair after cardiac injury is always the focus of research. However, in recent years, their dynamic changes and contributions in physiological states have a significant attention. CRMs have specific phenotypes and functions in different cardiac chambers or locations of the heart and at different stages. They further show specific differentiation and development processes. The present review will summarize the new progress about the spatiotemporal distribution, potential developmental regulation, and their roles in cardiac development and aging as well as the translational potential of CRMs on cardiac diseases. Of course, the research tools for CRMs, their respective advantages and disadvantages, and key issues on CRMs will further be discussed.

Correction: Enhancing Specific-Antibody Production to the ragB Vaccine with GITRL That Expand Tfh, IFN-γ+ T Cells and Attenuates Porphyromonas gingivalis Infection in Mice.

[This corrects the article DOI: 10.1371/journal.pone.0059604.].

Spatiotemporal development and the regulatory mechanisms of cardiac resident macrophages: Contribution in cardiac development and steady state.

Cardiac resident macrophages (CRMs) are integral components of the heart and play significant roles in cardiac development, steady-state, and injury. Advances in sequencing technology have revealed that CRMs are a highly heterogeneous population, with significant differences in phenotype and function at different developmental stages and locations within the heart. In addition to research focused on diseases, recent years have witnessed a heightened interest in elucidating the involvement of CRMs in heart development and the maintenance of cardiac function. In this review, we primarily concentrated on summarizing the developmental trajectories, both spatial and temporal, of CRMs and their impact on cardiac development and steady-state. Moreover, we discuss the possible factors by which the cardiac microenvironment regulates macrophages from the perspectives of migration, proliferation, and differentiation under physiological conditions. Gaining insight into the spatiotemporal heterogeneity and regulatory mechanisms of CRMs is of paramount importance in comprehending the involvement of macrophages in cardiac development, injury, and repair, and also provides new ideas and therapeutic methods for treating heart diseases.

Role of Histiocyte-Derived frHMGB1 as a Facilitator in Non-Canonical Pyroptosis of Monocytes/Macrophages in Lethal Sepsis.

In this study, we investigated the role of the non-canonical pyroptosis pathway in the progression of lethal sepsis. Our findings emphasize the significance of non-canonical pyroptosis in monocytes/macrophages for the survival of septic mice. We observed that inhibiting pyroptosis alone significantly improved the survival rate of septic mice, and the HMGB1 A box effectively suppressed this non-canonical pyroptosis, thereby enhancing the survival of septic mice. Additionally, our cell in vitro experiments further unveil that frHMGB1, originating from LPS-carrying histiocytes, enters macrophages via RAGE, resulting in the direct activation of caspase-11 and the induction of non-canonical pyroptosis. Notably, the A Box's competitive binding with LPS thereby impedes its entry into the cell cytosol. These findings reveal potential therapeutic strategies for slowing the progression of lethal sepsis by modulating the non-canonical pyroptosis pathway.

ILC2 influence the differentiation of alveolar type II epithelial cells in bronchopulmonary dysplasia mice.

Bronchopulmonary dysplasia, a common complication of premature infants, is mainly characterized by blocked alveolarization. Proverbially, the injury of alveolar type II epithelial cells is regarded as the pathologic basis of occurrence and development of bronchopulmonary dysplasia. In the case of alveolar epithelial damage, alveolar type II epithelial cells can also differentiate to alveolar type I epithelial cells as progenitor cells. During bronchopulmonary dysplasia, the differentiation of alveolar type II epithelial cells becomes abnormal. Group 2 innate lymphoid cells can produce type 2 cytokines in response to a variety of stimuli, including the epithelial cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Previous studies have shown that group 2 innate lymphoid cells can inhibit the alveolarization process of bronchopulmonary dysplasia by secreting IL-13. However, whether group 2 innate lymphoid cells can affect the differentiation of alveolar type II epithelial cells in the pathologic process of bronchopulmonary dysplasia remains unclear. In this study, we have shown that IL-13 secreted by group 2 innate lymphoid cells increased during bronchopulmonary dysplasia, which was related to the release of large amounts of IL-33 by impaired alveolar type II epithelial cells. This led to abnormal differentiation of alveolar type II epithelial cells, reduced differentiation to alveolar type I epithelial cells, and increased transdifferentiation to mesenchymal cells through the epithelial-mesenchymal transition. Taken together, our study provides a complementary understanding of the development of bronchopulmonary dysplasia and highlights a novel immune mechanism in the pathogenesis of bronchopulmonary dysplasia.

Insights into the roles of IL-10-producing regulatory B cells in cardiovascular disorders: recent advances and future perspectives.

Interleukin-10-producing regulatory B (B10) cells mediate the immunomodulatory functions of biosystems by secreting anti-inflammatory factors, thus playing vital roles in cardiovascular diseases such as viral myocarditis, myocardial infarction, and ischemia-reperfusion injury. However, several challenges hinder B10 cells from regulating the immunoreactivity of organisms in specific cardiovascular diseases, such as atherosclerotic disease. Regarding the regulatory mechanisms of B10 cells, the interplay between B10 cells and the cardiovascular and immune systems is complex and requires clarification. In this study, we summarize the roles of B10 cells in bacterial and aseptic heart injuries, address their regulatory functions in different stages of cardiovascular disorders, and discuss their challenges and opportunities in addressing cardiovascular diseases from bench to bedside.

S1PR1-dependent migration of ILC3s from intestinal tissue to the heart in a mouse model of viral myocarditis.

Type 3 innate lymphocytes have recently been reported as key factors in inflammatory diseases, but their role in viral myocarditis is unclear. By flow cytometry, coxsackievirus B3-induced myocarditis mice were detected to increase the number of type 3 innate lymphocytes, and their main type was NKp46+ type 3 innate lymphocytes. In contrast, application of CD90.2 neutralizing antibody in T-cell-deficient mice reduced the number of innate lymphocytes and improved myocarditis. Innate lymphocytes from CD45.1 mouse intestinal lamina propria lymphocytes were adoptively transferred into recipient mice, and a comparable proportion of CD45.1+ cells were observed in the hearts of coxsackievirus B3-infected recipient mice. The upregulation of S1PR1, KLF2, CXCR6, and CXCL16 in the hearts of coxsackievirus B3-infected mice, as well as the greatly reduced numbers of innate lymphocytes infiltrating the hearts after S1PR1 inhibition, suggests that intestinal innate lymphocytes may migrate to the hearts via the CXCL16/CXCR6 axis. Taken together, our results demonstrate that increased type 3 innate lymphocytes in the heart during viral myocarditis may contribute to inflammatory progression and that this increased population of type 3 innate lymphocytes likely originates from the intestine.

Bimetallic infinite coordination nanopolymers via phototherapy and STING activation for eliciting robust antitumor immunity.

Phototherapy can trigger immunogenic cell death of tumors in situ, whereas it is virtually impossible to eradicate the tumor due to the intrinsic resistance and inefficient anti-tumor immunity. To overcome these limitations, novel bimetallic infinite coordination nanopolymers (TA-Fe/Mn-OVA@MB NPs) were synthesized using model antigen ovalbumin (OVA) as a template to assemble tannic acid (TA) and bi-metal, supplemented with methylene blue (MB) surface absorption. The formulated TA-Fe/Mn-OVA@MB NPs possess excellent photothermal and photodynamic therapy (PTT/PDT) performance, which is adequate to destroy tumor cells by physical and chemical attack. Especially, these TA-Fe/Mn-OVA@MB NPs are capability of promoting the dendritic cells (DCs) maturation and antigen presentation via manganese-mediated cGAS-STING pathway activation, finally activating cytotoxicity T lymphocyte and promoting memory T lymphocyte differentiation in the peripheral lymphoid organs. In conclusion, this research offers a versatile metal-polyphenol nanoplatform to integrate functional metals and therapeutic molecule for topical phototherapy and robust anti-tumor immune activation.

Renewal of embryonic and neonatal-derived cardiac-resident macrophages in response to environmental cues abrogated their potential to promote cardiomyocyte proliferation via Jagged-1-Notch1.

Cardiac-resident macrophages (CRMs) play important roles in homeostasis, cardiac function, and remodeling. Although CRMs play critical roles in cardiac regeneration of neonatal mice, their roles are yet to be fully elucidated. Therefore, this study aimed to investigate the dynamic changes of CRMs during cardiac ontogeny and analyze the phenotypic and functional properties of CRMs in the promotion of cardiac regeneration. During mouse cardiac ontogeny, four CRM subsets exist successively: CX3CR1+CCR2-Ly6C-MHCII- (MP1), CX3CR1lowCCR2lowLy6C-MHCII- (MP2), CX3CR1-CCR2+Ly6C+MHCII- (MP3), and CX3CR1+CCR2-Ly6C-MHCII+ (MP4). MP1 cluster has different derivations (yolk sac, fetal liver, and bone marrow) and multiple functions population. Embryonic and neonatal-derived-MP1 directly promoted cardiomyocyte proliferation through Jagged-1-Notch1 axis and significantly ameliorated cardiac injury following myocardial infarction. MP2/3 subsets could survive throughout adulthood. MP4, the main population in adult mouse hearts, contributed to inflammation. During ontogeny, MP1 can convert into MP4 triggered by changes in the cellular redox state. These findings delineate the evolutionary dynamics of CRMs under physiological conditions and found direct evidence that embryonic and neonatal-derived CRMs regulate cardiomyocyte proliferation. Our findings also shed light on cardiac repair following injury.

Maternal colonization with group B Streptococcus and antibiotic resistance in China: systematic review and meta-analyses.

BACKGROUND: Maternal rectovaginal colonization with group B Streptococcus (GBS) or Streptococcus agalactiae is the most common pathway for this disease during the perinatal period. This meta-analysis aimed to summarize existing data regarding maternal colonization, serotype profiles, and antibiotic resistance in China. METHODS: Systematic literature reviews were conducted after searching 6 databases. Meta-analysis was applied to analyze colonization rate, serotype, and antimicrobial susceptibility of GBS clinical isolates in different regions of China. Summary estimates are presented using tables, funnel plots, forest plots, histograms, violin plots, and line plots. RESULTS: The dataset regarding colonization included 52 articles and 195 303 pregnant women. Our estimate for maternal GBS colonization in China was 8.1% (95% confidence interval [CI] 7.2%-8.9%). Serotypes Ia, Ib, III, and V account for 95.9% of identified isolates. Serotype III, which is frequently associated with the hypervirulent clonal complex, accounts for 46.4%. Among the maternal GBS isolates using multilocus sequence typing (MLST), ST19 (25.7%, 289/1126) and ST10 (25.1%, 283/1126) were most common, followed by ST12 (12.4%, 140/1126), ST17 (4.8%, 54/1126), and ST651 (3.7%, 42/1126). GBS was highly resistant to tetracycline (75.1% [95% CI 74.0-76.3%]) and erythromycin (65.4% [95% CI 64.5-66.3%]) and generally susceptible to penicillin, ampicillin, vancomycin, ceftriaxone, and linezolid. Resistance rates of GBS to clindamycin and levofloxacin varied greatly (1.0-99.2% and 10.3-72.9%, respectively). A summary analysis of the bacterial drug resistance reports released by the China Antimicrobial Resistance Surveillance System (CARSS) in the past 5 years showed that the drug resistance rate of GBS to erythromycin, clindamycin, and levofloxacin decreased slowly from 2018 to 2020. However, the resistance rates of GBS to all 3 antibiotics increased slightly in 2021. CONCLUSIONS: The overall colonization rate in China was much lower than the global colonization rate (17.4%). Consistent with many original and review reports in other parts of the world, GBS was highly resistant to tetracycline. However, the resistance of GBS isolates in China to erythromycin and clindamycin was greater than in other countries. This paper provides important epidemiological information, to assist with prevention and treatment of GBS colonization in these women.

HMGB1 is a Potential and Challenging Therapeutic Target for Parkinson's Disease.

Parkinson's disease (PD) is one of the most common degenerative diseases of the human nervous system and has a wide range of serious impacts on human health and quality of life. Recently, research targeting high mobility group box 1 (HMGB1) in PD has emerged, and a variety of laboratory methods for inhibiting HMGB1 have achieved good results to a certain extent. However, given that HMGB1 undergoes a variety of intracellular modifications and three different forms of extracellular redox, the possible roles of these forms in PD are likely to be different. General inhibition of all forms of HMGB1 is obviously not ideal and has become one of the biggest obstacles in the clinical application of targeting HMGB1. In this review, pure mechanistic research of HMGB1 and in vivo research targeting HMGB1 were combined, the effects of HMGB1 on neurons and immune cell responses in PD are discussed in detail, and the problems that need to be focused on in the future are addressed.

Bacterial strategies for immune systems - Role of the type VI secretion system.

The process of host infection by bacteria is complicated. Bacterial infections strongly induce the host immune system, which necessitates a robust clearance of the infection. However, bacteria have over time developed strategies that enable their evasion of attacks by the host immune system. One such strategy is the type VI secretion system (T6SS), a special needle-like secretion system that is widespread in Gram-negative bacteria and is responsible for delivering effector proteins into the external bacterial environment or directly into the host cell cytosol. Bacterial T6SS and its secreted effector proteins play an important role in the interaction between bacteria and host immune system. They also serve as antigens that are employed in the development of vaccines for clinical trials as well as future vaccine candidates. This review focuses mainly on aspects of T6SS effectors that impact the strength of the host immune system, including inflammation, autophagy, and apoptosis (silent programmed cell death). The T6SS-based vaccines are also described.

Endothelial derived miRNA-9 mediated cardiac fibrosis in diabetes and its regulation by ZFAS1.

Diabetic cardiomyopathy (DCM) is one of the most prevalent causes of morbidity and mortality in diabetic patients. Hyperglycemia induces increased expression/deposition of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (Col) and plays an important role in fibrosis in diabetic cardiomyopathy (DCM). The roles of RNAs including microRNA (miRNA) and long non-coding RNAs (lncRNA) have begun to be understood in many conditions. In this study, we investigated the role of a specific miRNA, miR-9, and its interactions with lncRNA ZFAS1 in mediating fibrosis in DCM. Treatment with 25 mM glucose (HG) decreased miR-9 expression and increased expressions of ZFAS1, ECM proteins and inflammatory markers, compared to 5 mM glucose (NG) in the HCMECs by using qRT-PCR. Glucose-induced upregulation of ECM proteins can be prevented by ZFAS1 siRNA or miR-9 mimic transfection. Luciferase assay was confirmed miR-9 binding to FN 3'-UTR. miR-9 expression can be regulated by ZFAS1 through polycomb repressive complex 2 (PRC2) components using RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays. In the in vivo experiment, hyperglycemia-induced the ECM production can be prevented by the miR-9 overexpression in the fibrosis in DCM. These studies showed a novel glucose-induced molecular mechanism in which ZFAS1 participates in the transcriptional regulation of ECM protein production in diabetes through miR-9.

Cardiac Mast Cells: A Two-Head Regulator in Cardiac Homeostasis and Pathogenesis Following Injury.

Cardiac mast cells (CMCs) are multifarious immune cells with complex roles both in cardiac physiological and pathological conditions, especially in cardiac fibrosis. Little is known about the physiological importance of CMCs in cardiac homeostasis and inflammatory process. Therefore, the present review will summarize the recent progress of CMCs on origin, development and replenishment in the heart, including their effects on cardiac development, function and ageing under physiological conditions as well as the roles of CMCs in inflammatory progression and resolution. The present review will shed a light on scientists to understand cardioimmunology and to develop immune treatments targeting on CMCs following cardiac injury.

A plant immune protein fights against cancer.

Altered global miRNA abundance is closely related to the occurrence of cancer. Recently, Qi et al. discovered that abnormal 1-nucleotide (nt)-shorter miRNA isoforms are widely accumulated in different human tumors. Ectopic expression of the plant immune protein RNA-dependent RNA polymerase (RDR)-1 can achieve a broad-spectrum antitumor effect by rescuing miRNA defects in cancer cells.

Sustained over-expression of calpain-2 induces age-dependent dilated cardiomyopathy in mice through aberrant autophagy.

Calpains have been implicated in heart diseases. While calpain-1 has been detrimental to the heart, the role of calpain-2 in cardiac pathology remains controversial. In this study we investigated whether sustained over-expression of calpain-2 had any adverse effects on the heart and the underlying mechanisms. Double transgenic mice (Tg-Capn2/tTA) were generated, which express human CAPN2 restricted to cardiomyocytes. The mice were subjected to echocardiography at age 3, 6, 8 and 12 months, and their heart tissues and sera were collected for analyses. We showed that transgenic mice over-expressing calpain-2 restricted to cardiomyocytes had normal heart function with no evidence of cardiac pathological remodeling at age 3 months. However, they exhibited features of dilated cardiomyopathy including increased heart size, enlarged heart chambers and heart dysfunction from age 8 months; histological analysis revealed loss of cardiomyocytes replaced by myocardial fibrosis and cardiomyocyte hypertrophy in transgenic mice from age 8 months. These cardiac alterations closely correlated with aberrant autophagy evidenced by significantly increased LC3BII and p62 protein levels and accumulation of autophagosomes in the hearts of transgenic mice. Notably, injection of 3-methyladenine, a well-established inhibitor of autophagy (30 mg/kg, i.p. once every 3 days starting from age 6 months for 2 months) prevented aberrant autophagy, attenuated myocardial injury and improved heart function in the transgenic mice. In cultured cardiomyocytes, over-expression of calpain-2 blocked autophagic flux by impairing lysosomal function. Furthermore, over-expression of calpain-2 resulted in lower levels of junctophilin-2 protein in the heart of transgenic mice and in cultured cardiomyocytes, which was attenuated by 3-methyladenine. In addition, blockade of autophagic flux by bafilomycin A (100 nM) induced a reduction of junctophilin-2 protein in cardiomyocytes. In summary, transgenic over-expression of calpain-2 induces age-dependent dilated cardiomyopathy in mice, which may be mediated through aberrant autophagy and a reduction of junctophilin-2. Thus, a sustained increase in calpain-2 may be detrimental to the heart.

ANRIL regulates multiple molecules of pathogenetic significance in diabetic nephropathy.

BACKGROUND: Hyperglycemia-induced transcriptional alterations lead to aberrant synthesis of a large number of pathogenetic molecules leading to functional and structural damage to multiple end organs including the kidneys. Diabetic nephropathy (DN) remains a major cause of end stage renal disease. Multiple epigenetic mechanisms, including alteration of long non-coding RNAs (lncRNAs) may play a significant role mediating the cellular transcriptional activities. We have previously shown that lncRNA ANRIL may mediate diabetes associated molecular, functional and structural abnormalities in DN. Here we explored downstream mechanisms of ANRIL alteration in DN. METHODS: We used renal cortical tissues from ANRIL knockout (KO) mice and wild type (WT) mice, with or without streptozotocin (STZ) induced diabetes for RNA sequencing. The differentially expressed genes were identified using edgeR and DESeq2 computational methods. KEGG and Reactome pathway analyses and network analyses using STRING and IPA were subsequently performed. RESULTS: Diabetic animals showed hyperglycemia, reduced body weight gain, polyuria and increased urinary albumin. Both albuminuria and polyuria were corrected in the KO diabetic mice. RNA analyses showed Diabetes induced alterations of a large number of transcripts in the wild type (WT) animals. ANRIL knockout (KO) prevented a large number of such alterations. The altered transcripts include metabolic pathways, apoptosis, extracellular matrix protein synthesis and degradation, NFKB related pathways, AGE-RAGE interaction pathways etc. ANRIL KO prevented majority of these pathways. CONCLUSION: These findings suggest that as ANRIL regulates a large number of molecules of pathogenetic significance, it may potentially be a drug target for DN and other chronic diabetic complications.

In Silico and In Vitro Screening of Natural Compounds as Broad-Spectrum ß-Lactamase Inhibitors against Acinetobacter baumannii New Delhi Metallo-ß-lactamase-1 (NDM-1).

Antibiotic resistance is one of the significant problems globally; there is an increase in resistance with introducing every new class of antibiotics. Further, this has become one of the reasons for arising of new resistance mechanisms in Acinetobacter baumannii. In this study, we have screened natural compounds as a possible inhibitor against the NDM-1 ß-lactamase enzyme from A. baumannii using a combination of in silico methods and in vitro evaluation. The database of natural compounds was screened against NDM-1 protein, using Glide docking, followed by QM-polarised ligand docking (QPLD). When the screened hits were validated in vitro, withaferin A and mangiferin had good IC50 values in reducing the activity of NDM-1 enzymes, and their fractional inhibitory concentration index (FICI) was ascertained in combination with imipenem. The withaferin A and mangiferin-NDM-1 docking complexes were analyzed for structural stability by molecular dynamic simulation analysis using GROMACS for 100 ns. The molecular properties of the natural compounds were then calculated using density functional theory (DFT). Withaferin A and mangiferin showed promising inhibitory activity and can be a natural compound candidate inhibitor synergistically used along with carbapenems against NDM-1 producing A. baumannii.