Amphiregulin improves ventricular remodeling after myocardial infarction by modulating autophagy and apoptosis.

Myocardial infarction (MI) is defined as sudden ischemic death of myocardial tissue. Amphiregulin (Areg) regulates cell survival and is crucial for the healing of tissues after damage. However, the functions and mechanisms of Areg after MI remain unclear. Here, we aimed to investigate Areg's impact on myocardial remodeling. Mice model of MI was constructed and Areg-/- mice were used. Expression of Areg was analyzed using western blotting, RT-qPCR, flow cytometry, and immunofluorescence staining. Echocardiographic analysis, Masson's trichrome, and triphenyltetrazolium chloride staining were used to assess cardiac function and structure. RNA sequencing was used for unbiased analysis. Apoptosis and autophagy were determined by western blotting, TUNEL staining, electron microscopy, and mRFP-GFP-LC3 lentivirus. Lysosomal acidity was determined by Lysotracker staining. Areg was elevated in the infarct border zone after MI. It was mostly secreted by macrophages. Areg deficiency aggravated adverse ventricular remodeling, as reflected by worsening cardiac function, a lower survival rate, increased scar size, and interstitial fibrosis. RNA sequencing analyses showed that Areg related to the epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR) signaling pathways, V-ATPase and lysosome pathways. Mechanistically, Areg exerts beneficial effects via increasing lysosomal acidity to promote autophagosome clearance, and activating the EGFR/PI3K/Akt/mTOR signaling pathway, subsequently inhibiting excessive autophagosome formation and apoptosis in cardiomyocytes. This study provides a novel evidence for the role of Areg in inhibiting ventricular remodeling after MI by regulating autophagy and apoptosis and identifies Areg as a potential therapeutic target in ventricular remodeling after MI.

Increased expression of protein tyrosine phosphatase nonreceptor type 22 alters early T-cell receptor signaling and differentiation of CD4+ T cells in chronic heart failure.

CD4+ T-cell counts are increased and activated in patients with chronic heart failure (CHF), whereas regulatory T-cell (Treg) expansion is inhibited, probably due to aberrant T-cell receptor (TCR) signaling. TCR signaling is affected by protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in autoimmune disorders, but whether PTPN22 influences TCR signaling in CHF remains unclear. This observational case-control study included 45 patients with CHF [18 patients with ischemic heart failure versus 27 patients with nonischemic heart failure (NIHF)] and 16 non-CHF controls. We used flow cytometry to detect PTPN22 expression, tyrosine phosphorylation levels, zeta-chain-associated protein kinase, 70 kDa (ZAP-70) inhibitory residue tyrosine 292 and 319 phosphorylation levels, and CD4+ T cell and Treg proportions. We conducted lentivirus-mediated PTPN22 RNA silencing in isolated CD4+ T cells. PTPN22 expression increased in the CD4+ T cells of patients with CHF compared with that in controls. PTPN22 expression was positively correlated with left ventricular end-diastolic diameter and type B natriuretic peptide but negatively correlated with left ventricular ejection fraction in the NIHF group. ZAP-70 tyrosine 292 phosphorylation was decreased, which correlated positively with PTPN22 overexpression in patients with NIHF and promoted early TCR signaling. PTPN22 silencing induced Treg differentiation in CD4+ T cells from patients with CHF, which might account for the reduced frequency of peripheral Tregs in these patients. PTPN22 is a potent immunomodulator in CHF and might play an essential role in the development of CHF by promoting early TCR signaling and impairing Treg differentiation from CD4+ T cells.

Unravelling CD4+ T cell diversity and tissue adaptation of Tregs in abdominal aortic aneurysms through single-cell sequencing.

Immune cell infiltration is a significant pathological process in abdominal aortic aneurysms (AAA). T cells, particularly CD4+ T cells, are essential immune cells responsible for substantial infiltration of the aorta. Regulatory T cells (Tregs) in AAA have been identified as tissue-specific; however, the time, location, and mechanism of acquiring the tissue-specific phenotype are still unknown. Using single-cell RNA sequencing (scRNA-seq) on CD4+ T cells from the AAA aorta and spleen, we discovered heterogeneity among CD4+ T cells and identified activated, proliferating and developed aorta Tregs. These Tregs originate in the peripheral tissues and acquire the tissue-specific phenotype in the aorta. The identification of precursors for Tregs in AAA provides new insight into the pathogenesis of AAA.

Cholesterol suppresses human iTreg differentiation and nTreg function through mitochondria-related mechanisms.

BACKGROUND: Both the crystalline and soluble forms of cholesterol increase macrophage secretion of interleukin 1ß (IL-1ß), aggravating the inflammatory response in atherosclerosis (AS). However, the link between cholesterol and regulatory T cells (Tregs) remains unclear. This study aimed to investigate the effect of cholesterol treatment on Tregs. METHODS: Differentiation of induced Tregs (iTregs) was analyzed using flow cytometry. The expression of hypoxia-inducible factor-1a (HIF-1a) and its target genes was measured by western blotting and/or RT-qPCR. Two reporter jurkat cell lines were constructed by lentiviral transfection. Mitochondrial function and the structure of natural Tregs (nTregs) were determined by tetramethylrhodamine (TMRM) and mitoSOX staining, Seahorse assay, and electron microscopy. The immunoregulatory function of nTregs was determined by nTreg-macrophage co-culture assay and ELISA. RESULTS: Cholesterol treatment suppressed iTreg differentiation and impaired nTreg function. Mechanistically, cholesterol induced the production of mitochondrial reactive oxygen species (mtROS) in naïve T cells, inhibiting the degradation of HIF-1α and unleashing its inhibitory effects on iTreg differentiation. Furthermore, cholesterol-induced mitochondrial oxidative damage impaired the immunosuppressive function of nTregs. Mixed lymphocyte reaction and nTreg-macrophage co-culture assays revealed that cholesterol treatment compromised the ability of nTregs to inhibit pro-inflammatory conventional T cell proliferation and promote the anti-inflammatory functions of macrophages. Finally, mitoTEMPO (MT), a specific mtROS scavenger, restored iTreg differentiation and protected nTreg from further deterioration. CONCLUSION: Our findings suggest that cholesterol may aggravate inflammation within AS plaques by acting on both iTregs and nTregs, and that MT may be a promising anti-atherogenic drug.

Pleural mesothelial cell migration into lung parenchyma by calpain contributes to idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia. It is unknown why fibrosis in IPF distributes in the peripheral or named sub-pleural area. Migration of pleural mesothelial cells (PMC) should contribute to sub-pleural fibrosis. Calpain is known to be involved in cell migration, but the role of calpain in PMC migration has not been investigated. In this study, we found that PMCs migrated into lung parenchyma in patients with IPF. Then using Wt1tm1(EGFP/Cre)Wtp /J knock-in mice, we observed PMC migration into lung parenchyma in bleomycin-induced pleural fibrosis models, and calpain inhibitor attenuated pulmonary fibrosis with prevention of PMC migration. In vitro studies revealed that bleomycin and transforming growth factor-ß1 increased calpain activity in PMCs, and activated calpain-mediated focal adhesion (FA) turnover as well as cell migration, cell proliferation, and collagen-I synthesis. Furthermore, we determined that calpain cleaved FA kinase in both C-terminal and N-terminal regions, which mediated FA turnover. Lastly, the data revealed that activated calpain was also involved in phosphorylation of cofilin-1, and p-cofilin-1 induced PMC migration. Taken together, this study provides evidence that calpain mediates PMC migration into lung parenchyma to promote sub-pleural fibrosis in IPF.

A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction.

BACKGROUND: Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype, and function of so-called tissue Tregs in the heart remain unclear. METHODS: In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury, or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or ischemia/reperfusion injury. Photoconversion, parabiosis, single-cell T-cell receptor sequencing, and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin-33/suppression of tumorigenicity 2 axis and Sparc (secreted acidic cysteine-rich glycoprotein), a molecule upregulated in heart Tregs, was further evaluated in functional assays. RESULTS: We showed that Tregs were highly enriched in the myocardium of MI, ischemia/reperfusion injury, and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts in comparison with their lymphoid counterparts, including heart-draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly because of recruitment from the circulating Treg pool, whereas local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected T-cell receptor of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, HelioshighNrp-1high phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4+ T cells, proved by the analysis of T-cell receptor repertoires and conventional CD4+ T cells adoptive transfer experiments. The interleukin-33/suppression of tumorigenicity 2 axis was essential for sustaining heart Treg populations. Last, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone. CONCLUSIONS: We identified and characterized a phenotypically and functionally unique population of heart Tregs that may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.

VEGF/Src signaling mediated pleural barrier damage and increased permeability contributes to subpleural pulmonary fibrosis.

The distribution of fibrosis in idiopathic pulmonary fibrosis (IPF) is subpleural with basal predominance. Alveolar epithelial cell was considered as the key cell in the initial phase of IPF. However, the idea of activation and damage of alveolar epithelial cells is very difficult to explain why fibrosis distributes in the subpleural area. In this study, human pleural mesothelial cell (PMC) line and primary rat PMC was used as in vitro model. Intraperitoneal injection of bleomycin was used for making a pulmonary fibrosis model. The integrity of cultured monolayer PMCs was determined by transepithelial electric resistance (TEER). Pleural permeability was estimated by measuring paracellular transport of fluorescein isothiocyanate (FITC)-conjugated dextran. Changes in lung tissue of patients with IPF were analyzed by Masson's and immunofluorescence staining. We found bleomycin induced PMCs damage and increased PMCs permeability; increased PMCs permeability aggravated bleomycin-induced subpleural inflammation and pulmonary fibrosis. Moreover, bleomycin was found to activate VEGF/Src signaling which increased PMCs permeability. In vivo, inhibition of VEGF/Src signaling prevented bleomycin-induced subpleural pulmonary fibrosis. At last, activation of VEGF/Src signaling was confirmed in subpleural area in patients with IPF. Taken together, our findings indicate that VEGF/Src signaling mediated pleural barrier damage and increased permeability which contributes to subpleural pulmonary fibrosis.

Regulatory B cells improve ventricular remodeling after myocardial infarction by modulating monocyte migration.

Overactivated inflammatory responses contribute to adverse ventricular remodeling after myocardial infarction (MI). Regulatory B cells (Bregs) are a newly discovered subset of B cells with immunomodulatory roles in many immune and inflammation-related diseases. Our study aims to determine whether the expansion of Bregs exerts a beneficial effect on ventricular remodeling and explore the mechanisms involved. Here, we showed that adoptive transfer of Bregs ameliorated ventricular remodeling in a murine MI model, as demonstrated by improved cardiac function, decreased scar size and attenuated interstitial fibrosis without changing the survival rate. Reduced Ly6Chi monocyte infiltration was found in the hearts of the Breg-transferred mice, while the infiltration of Ly6Clo monocytes was not affected. In addition, the replenishment of Bregs had no effect on the myocardial accumulation of T cells or neutrophils. Mechanistically, Bregs reduced the expression of C-C motif chemokine receptor 2 (CCR2) in monocytes, which inhibited proinflammatory monocyte recruitment to the heart from the peripheral blood and mobilization from the bone marrow. Breg-mediated protection against MI was abrogated by treatment with an interleukin 10 (IL-10) antibody. Finally, IL-10 neutralization reversed the effect of Bregs on monocyte migration and CCR2 expression. The present study suggests a therapeutic value of Bregs in limiting ventricular remodeling after MI through decreasing CCR2-mediated monocyte recruitment and mobilization.

Anti-tumor compounds identification from gossypol Groebke imidazopyridine product.

Series of imidazo[1,2-a]pyridines designed from gossypol modification based on Groebke-Blackburn-Bienaymé reaction were discovered as potent Bcl-2 inhibitors. Compound 4 was found to display good anti-proliferative activities for 7 human cancer cell lines (0.33-1.7 µM) among them, which were better than separate gossypol and imidazopyridine moiety compounds. It was capable of suppressing antiapoptotic proteins Bcl-2 and Bcl-XL demonstrated by mechanism studies, and possible binding model was also illustrated by molecular modelling.

Bleomycin induced apical-basal polarity loss in alveolar epithelial cell contributes to experimental pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrosing interstitial lung disease with limited therapeutic options and a median survival of 3 years after diagnosis. Dysregulated epithelial regeneration is key event involved in initiating and sustaining IPF. The type II alveolar epithelial cells (AECIIs) play a crucial role for epithelial regeneration and stabilisation of alveoli. Loss of cell apical-basal polarity contributes to fibrosis. AECII has apical-basal polarity, but it is poorly understood whether AECII apical-basal polarity loss is involved in fibrosis. Bleomycin is a traditional inducer of pulmonary fibrosis. Here firstly we observed that bleomycin induced apical-basal polarity loss in cultured AECIIs. Next, cell polarity proteins lethal (2) giant larvae 1 (Lgl1), PAR-3A, aPKC and PAR-6B were investigated. We found bleomycin induced increases of Lgl1 protein and decreases of PAR-3A protein, and bleomycin-induced PAR-3A depression was mediated by increased-Lgl1. Then Lgl1 siRNA was transfected into AECIIs. Lgl1 siRNA prevented apical-basal polarity loss in bleomycin-treated AECIIs. At last, Lgl1-conditional knockout mice were applied in making animal models. Bleomycin induced pulmonary fibrosis, but this was attenuated in Lgl1-conditional knockout mice. Together, these data indicated that bleomycin mediated AECII apical-basal polarity loss which contributed to experimental pulmonary fibrosis. Inhibition of Lgl1 should be a potential therapeutic strategy for the disease.

IL (Interleukin)-33 Suppresses Abdominal Aortic Aneurysm by Enhancing Regulatory T-Cell Expansion and Activity.

Objective- Inflammation occurs during the progression of abdominal aortic aneurysm (AAA). IL (interleukin)-33 is a pleiotropic cytokine with multiple immunomodulatory effects, yet its role in AAA remains unknown. Approach and Results- Immunoblot, immunohistochemistry, and immunofluorescent staining revealed increased IL-33 expression in adventitia fibroblasts from mouse AAA lesions. Daily intraperitoneal administration of recombinant IL-33 or transgenic IL-33 expression ameliorated periaorta CaPO4 injury- and aortic elastase exposure-induced AAA in mice, as demonstrated by blunted aortic expansion, reduced aortic wall elastica fragmentation, enhanced AAA lesion collagen deposition, attenuated T-cell and macrophage infiltration, reduced inflammatory cytokine production, skewed M2 macrophage polarization, and reduced lesion MMP (matrix metalloproteinase) expression and cell apoptosis. Flow cytometry analysis, immunostaining, and immunoblot analysis showed that exogenous IL-33 increased CD4+Foxp3+ regulatory T cells in spleens, blood, and aortas in periaorta CaPO4-treated mice. Yet, ST2 deficiency muted these IL-33 activities. Regulatory T cells from IL-33-treated mice also showed significantly stronger activities in suppressing smooth muscle cell inflammatory cytokine and chemokine expression, macrophage MMP expression, and in increasing M2 macrophage polarization than those from vehicle-treated mice. In contrast, IL-33 failed to prevent AAA and lost its beneficial activities in CaPO4-treated mice after selective depletion of regulatory T cells. Conclusions- Together, this study established a role of IL-33 in protecting mice from AAA formation by enhancing ST2-dependent aortic and systemic regulatory T-cell expansion and their immunosuppressive activities.

Defective Circulating Regulatory B Cells in Patients with Dilated Cardiomyopathy.

BACKGROUND/AIMS: Newly identified IL-10-producing regulatory B cells (Bregs) have been shown to play an important role in the suppression of immune responses. Chronic immune activation participates in the pathogenesis of dilated cardiomyopathy (DCM) but whether Bregs are involved in its development remains unclear. We aimed to investigate the circulating frequency and function of Bregs in DCM. METHODS: In total, 35 DCM patients (20 men and 15 women) and 44 healthy controls (23 men and 21 women) were included in the experiment, and the frequency of Bregs was detected using flow cytometry. RESULTS: According to our results, the frequency of circulating IL-10-producing Bregs was significantly lower in DCM patients compared with healthy controls. Furthermore, the CD24hiCD27+ B cell subset in which IL-10-producing Bregs were mainly enriched from DCM patients showed impaired IL-10 expression and a decreased ability to suppress the TNF-α production of CD4+CD25- Tconv cells and to maintain Tregs differentiation. Correlation analysis showed that the frequency of IL-10-producing Bregs and the suppressive function of CD24hiCD27+ B cells were positively correlated with left ventricular ejection fraction and negatively correlated with NT-proBNP in DCM patients. CONCLUSIONS: In conclusion, the reduced frequency and impaired functions suggest a potential role of Bregs in the development of DCM.

Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis.

Pleural fibrosis is defined as an excessive deposition of extracellular matrix (ECM) components that results in destruction of the normal pleural tissue architecture. It can result from diverse inflammatory conditions, especially tuberculous pleurisy. Pleural mesothelial cells (PMCs) play a pivotal role in pleural fibrosis. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodeling. However, the role of calpain in pleural fibrosis remains unknown. In the present study, we found that tuberculous pleural effusion (TPE) induced calpain activation in PMCs and that inhibition of calpain prevented TPE-induced collagen-I synthesis and cell proliferation of PMCs. Moreover, our data revealed that the levels of angiotensin (ANG)-converting enzyme (ACE) were significantly higher in pleural fluid of patients with TPE than those with malignant pleural effusion, and ACE-ANG II in TPE resulted in activation of calpain and subsequent triggering of the phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB signaling pathway in PMCs. Finally, calpain activation in PMCs and collagen depositions were confirmed in pleural biopsy specimens from patients with tuberculous pleurisy. Together, these studies demonstrated that calpain is activated by renin-angiotensin system in pleural fibrosis and mediates TPE-induced collagen-I synthesis and proliferation of PMCs via the PI3K/Akt/NF-κB signaling pathway. Calpain in PMCs might be a novel target for intervention in tuberculous pleural fibrosis.

Activated regulatory T-cells attenuate myocardial ischaemia/reperfusion injury through a CD39-dependent mechanism.

Regulatory T-cells (Tregs) are generally regarded as key immunomodulators that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. However, its role in myocardial ischaemia/reperfusion injury (MIRI) remains unknown. The purpose of the present study was to determine whether Tregs exert a beneficial effect on mouse MIRI. We examined the role of Tregs in murine MIRI by depletion using 'depletion of regulatory T-cell' (DEREG) mice and adoptive transfer using Forkhead box P3 (Foxp3)-GFP knockin mice and the mechanisms of cardio protection were further studied in vivo and in vitro. Tregs rapidly accumulated in murine hearts following MIRI. Selective depletion of Tregs in the DEREG mouse model resulted in aggravated MIRI. In contrast, the adoptive transfer of in vitro-activated Tregs suppressed MIRI, whereas freshly isolated Tregs had no effect. Mechanistically, activated Treg-mediated protection against MIRI was not abrogated by interleukin (IL)-10 or transforming growth factor (TGF)-ß1 inhibition but was impaired by the genetic deletion of cluster of differentiation 39 (CD39). Moreover, adoptive transfer of in vitro-activated Tregs attenuated cardiomyocyte apoptosis, activated a pro-survival pathway involving Akt and extracellular-signal-regulated kinase (ERK) and inhibited neutrophil infiltration, which was compromised by CD39 deficiency. Finally, the peripheral blood mononuclear cells of acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (PCI) revealed a decrease in CD4+CD25+CD127low Tregs and a relative increase in CD39+ cells within the Treg population. In conclusion, our data validated a protective role for Tregs in MIRI. Moreover, in vitro-activated Tregs ameliorated MIRI via a CD39-dependent mechanism, representing a putative therapeutic strategy.

An Automated Strategy to Calculate Medication Regimen Complexity.

Understanding medication regimen complexity is important to understand what patients may benefit from pharmacist interventions. Medication Regimen Complexity Index (MRCI), a 65-item tool to quantify the complexity by incorporating the count, dosage form, frequency, and additional administration instructions of prescription medicines, provides a more nuanced way of assessing complexity. The goal of this study was to construct and validate a computational strategy to automate the calculation of MRCI. The performance of our strategy was evaluated by comparing our calculated MRCI values with gold-standard values, using correlation coefficients and population distributions. The results revealed satisfactory performance to calculate the sub-score of MRCI that includes dosage form and frequency (76 to 80% match with gold standard), and fair performance for sub-score related to additional direction (52% match with gold standard). Our automated strategy shows potential to help reduce the effort for manually calculating MRCI and highlights areas for future development efforts.

Practical Strategy to 1,1'-Dideoxygossypol Derivatives from Gossypol and Its Antitumor Activities.

A practical and scalable route for the synthesis of 1,1'-dideoxygossypol from natural polyphenol product gossypol is described. The key step is the successful regioselective deacetylation of hexaacetyl apogossypol 9 and the following reductive removal of hydroxyl groups. The two steps of deacetylation occurred on the different sites under different conditions. The synthetic route follows a simple protection-deprotection strategy, and the yields of each step are over 85%. The total yield of this 9-step synthesis is over 40%, which is much better than the reported total synthesis method. The antitumor results illustrate that 1,1'-hydroxyl groups are not necessary for antitumor activities. In addition, 1,1'-dideoxygossypol has superior aqueous solubility (215 mg/L) compared to gossypol (64 mg/L).

Aorta Regulatory T Cells with a Tissue-Specific Phenotype and Function Promote Tissue Repair through Tff1 in Abdominal Aortic Aneurysms.

In addition to maintaining immune tolerance, Foxp3+ regulatory T cells (Tregs) perform specialized functions in tissue homeostasis and remodeling. However, whether Tregs in aortic aneurysms have a tissue-specific phenotype and function is unclear. Here, a special group of Tregs that potentially inhibit abdominal aortic aneurysm (AAA) progression are identified and functionally characterized. Aortic Tregs gradually increase during the process of AAA and are mainly recruited from peripheral circulation. Single-cell TCR sequencing and bulk RNA sequencing demonstrate their unique phenotype and highly expressed trefoil factor 1 (Tff1). Foxp3cre/cre Tff1flox/flox mice are used to clarify the role of Tff1 in AAA, suggesting that aortic Tregs secrete Tff1 to regulate smooth muscle cell (SMC) survival. In vitro experiments confirm that Tff1 inhibits SMC apoptosis through the extracellular signal-regulated kinase (ERK) 1/2 pathway. The findings reveal a tissue-specific phenotype and function of aortic Tregs and may provide a promising and novel approach for the prevention of AAA.

Propionate Alleviates Abdominal Aortic Aneurysm by Modulating Colonic Regulatory T-Cell Expansion and Recirculation.

Emerging evidence supports that intestinal microbial metabolite short-chain fatty acids (SCFAs) increase the pool of regulatory T cells (Tregs) in the colonic lamina propria (cLP) and protect against nonintestinal inflammatory diseases, such as atherosclerosis and post-infarction myocardial inflammation. However, whether and how SCFAs protect the inflamed aortas of subjects with abdominal aortic aneurysm (AAA) remains unclear. Here, the authors revealed the protective effect of SCFAs on AAA in mice and the expansion of Tregs in the cLP, and propionate exerted Treg-dependent protection against AAA by promoting the recirculation of cLP-Tregs through colonic draining lymph nodes (dLNs) to the inflamed aorta.

Blockade of phosphotyrosine pathways suggesting SH2 superbinder as a novel therapy for pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic disease with high mortality. Currently, pirfenidone and nintedanib are the only approved drugs for IPF by the U.S. Food and Drug Administration (FDA), but their efficacy is limited. The activation of multiple phosphotyrosine (pY) mediated signaling pathways underlying the pathological mechanism of IPF has been explored. A Src homology-2 (SH2) superbinder, which contains mutations of three amino acids (AAs) of natural SH2 domain has been shown to be able to block phosphotyrosine (pY) pathway. Therefore, we aimed to introduce SH2 superbinder into the treatment of IPF. Methods: We analyzed the database of IPF patients and examined pY levels in lung tissues from IPF patients. In primary lung fibroblasts obtained from IPF patient as well as bleomycin (BLM) treated mice, the cell proliferation, migration and differentiation associated with pY were investigated and the anti-fibrotic effect of SH2 superbinder was also tested. In vivo, we further verified the safety and effectiveness of SH2 superbinder in multiple BLM mice models. We also compared the anti-fibrotic effect and side-effect of SH2 superbinder and nintedanib in vivo. Results: The data showed that the cytokines and growth factors pathways which directly correlated to pY levels were significantly enriched in IPF. High pY levels were found to induce abnormal proliferation, migration and differentiation of lung fibroblasts. SH2 superbinder blocked pY-mediated signaling pathways and suppress pulmonary fibrosis by targeting high pY levels in fibroblasts. SH2 superbinder had better therapeutic effect and less side-effect compare to nintedanib in vivo. Conclusions: SH2 superbinder had significant anti-fibrotic effects both in vitro and in vivo, which could be used as a promising therapy for IPF.

Regulatory T Cells in Chronic Heart Failure.

Heart failure is a global problem with high hospitalization and mortality rates. Inflammation and immune dysfunction are involved in this disease. Owing to their unique function, regulatory T cells (Tregs) have reacquired attention recently. They participate in immunoregulation and tissue repair in the pathophysiology of heart failure. Tregs are beneficial in heart by suppressing excessive inflammatory responses and promoting stable scar formation in the early stage of heart injury. However, in chronic heart failure, the phenotypes and functions of Tregs changed. They transformed into an antiangiogenic and profibrotic cell type. In this review, we summarized the functions of Tregs in the development of chronic heart failure first. Then, we focused on the interactions between Tregs and their target cells. The target cells of Tregs include immune cells (such as monocytes/macrophages, dendritic cells, T cells, and B cells) and parenchymal cells (such as cardiomyocytes, fibroblasts, and endothelial cells). Next-generation sequencing and gene editing technology make immunotherapy of heart failure possible. So, prospective therapeutic approaches based on Tregs in chronic heart failure had also been evaluated.