Neutrophilic asthma is a steroid-resistant condition linked to immunometabolic dysregulation. While the NAD+-dependent deacetylase Sirtuin 6 (SIRT6) regulates immune responses, its role in neutrophilic asthma remains unknown. Utilizing multiple human samples and neutrophilic asthma murine model, we identify macrophage SIRT6 as a key regulator that governs airway neutrophil infiltration in severe asthma. Myeloid-specific Sirt6 deletion attenuates allergen-induced airway neutrophil infiltration by suppressing lactate dehydrogenase A (LDHA)-mediated lactate production and neutrophil-recruiting chemokines secretion. Mechanistically, SIRT6 directly interacts with LDHA and deacetylates LDHA at lysine 261 (K261) via SIRT6-N-terminal domain. Lactate accumulation promotes histone H4 lysine 12 (H4K12) lactylation, up-regulating Cxcl1 and Cxcl2 transcription to drive airway neutrophil infiltration. Importantly, we screen flavonoid astragalin as a specific SIRT6 inhibitor that attenuates airway neutrophil infiltration in severe asthmatic mice. Collectively, our findings reveal a critical role of the SIRT6-mediated metabolic reprogramming in neutrophilic asthma and establish SIRT6 as a promising therapeutic target.

Severe asthma frequently manifests as a neutrophilic phenotype associated with dysregulated Th17 cell response, yet the molecular mechanism regulating Th17 cell-driven pathology remain poorly defined. Here, we identified histone deacetylase (HDAC) 10 as a critical regulator of Th17 cell differentiation in severe asthma. HDAC10 expression in CD4+ T cells was upregulated in asthmatic mice and patients with asthma. CD4+ T cell-specific deletion of Hdac10 attenuated neutrophilic airway inflammation by dampening Th17 cell differentiation and subsequent IL-17A secretion. Mechanistically, HDAC10 directly bound to signal transducer and activator of transcription 3 (STAT3) and deacetylated it at lysine 631 (K631) in Th17 cells, a post-translational modification essential for Il-17a transcription and subsequent neutrophilic airway inflammation. Importantly, pharmacological inhibition of HDAC10 abrogated Th17 cell response and neutrophilic airway inflammation. Together, our findings reveal an unrecognized role for HDAC10 in governing Th17 cell pathogenicity, highlighting HDAC10 as a promising therapeutic target for severe asthma.

Chronic airway inflammation is a central driver of asthma pathogenesis, in which macrophages play a pivotal role. While autophagy is known to regulate macrophage function, the specific molecular mechanisms linking autophagy to allergic airway inflammation remain unclear. Here, we identify macrophage sirtuin 6 (SIRT6) as a critical regulator of autophagy and allergic inflammation in asthma. SIRT6 expression was elevated in lung tissues and macrophages from asthmatic mice. Myeloid-specific Sirt6 deletion attenuated allergic airway inflammation in asthma murine model. Mechanistically, SIRT6 promoted proinflammatory cytokine expression via autophagy-related 3 (ATG3)-mediated autophagy in macrophages. We further demonstrated that SIRT6 directly bound to ATG3 and deacetylated it at lysine 77 (K77), a modification required for driving the proinflammatory response. Importantly, pharmacological inhibition of SIRT6 with OSS_128167 suppressed macrophage autophagy and alleviated allergic inflammation. Our findings establish SIRT6 as a key promoter of allergic airway inflammation through ATG3 deacetylation and enhanced autophagy in macrophages, highlighting SIRT6 inhibition as a potential novel therapeutic strategy for asthma.

The differential diagnosis of tuberculous pleural effusion (TPE) and lung adenocarcinoma-associated malignant pleural effusion (LA-MPE) remains challenging. This study aimed to measure interleukin‑9 (IL‑9) levels in pleural fluid and evaluate its diagnostic utility in distinguishing between these two conditions. The study enrolled 105 patients with PE (51 TPE and 54 LA-MPE). IL-9 levels in pleural fluid were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis was employed to identify the optimal cutoff value and assess diagnostic performance, including area under the curve (AUC), sensitivity, and specificity, with adenosine deaminase (ADA) and carcinoembryonic antigen (CEA) as comparators. Internal cross-validation was conducted to examine model robustness, and decision curve analysis was used to evaluate the clinical net benefit of IL-9 alone and in combination with ADA and CEA. IL-9 levels were significantly elevated in TPE compared with LA-MPE (2828.13 vs. 310.55 ng/L, P < 0.001). At a cutoff of 748.47 ng/L, IL-9 distinguished TPE from LA-MPE with a sensitivity of 98.0

Dysregulated macrophage polarization is a pivotal driver of airway inflammation in asthma, yet the underlying molecular mechanisms remain incompletely understood. Here, we demonstrate that histone acetyltransferase KAT8 exacerbates allergic airway inflammation by promoting M2 macrophage polarization in asthma. KAT8 expression was significantly upregulated in lung macrophages of asthmatic mice and in bone marrow-derived macrophages (BMDMs) stimulated with house dust mite (HDM). Macrophage-specific KAT8 deficiency attenuated allergic airway inflammation and inhibited M2 macrophage polarization by suppressing signal transducer and activator of transcription 3 (STAT3) signaling. Mechanistically, KAT8 directly interacted with STAT3 and targeted it for acetylation, thereby driving M2 macrophage polarization. Importantly, pharmacological inhibition of KAT8 reduced M2 macrophage polarization and attenuated allergic airway inflammation. These findings establish KAT8 as a critical regulator of macrophage-driven allergic inflammation via STAT3 acetylation, highlighting its potential as a therapeutic target for asthma.

Understanding p53-independent regulatory mechanisms is crucial for predicting outcomes in lung adenocarcinoma (LUAD) and developing improved therapeutic strategies. We found that PDLIM4 is highly expressed in LUAD tumor tissues, where it induces G2/M phase cell cycle arrest and suppresses cell proliferation, suggesting its potential role in improving patient prognosis. Our study identified BRD4, a bromodomain and extraterminal (BET) family protein, as a key transcriptional regulator of PDLIM4, acting through its BD1 domain. Further analysis revealed that wild-type PDLIM4 stabilizes p21 by blocking its RNA degradation, leading to p21 protein accumulation and subsequent inhibition of cell proliferation. In contrast, the S116 mutation in PDLIM4 abrogates this regulatory effect. Notably, activation of the BRD4/PDLIM4/p21 pathway enhanced chemosensitivity to doxorubicin in both LUAD cells and xenograft tumor models. Given the high mutation frequency of PDLIM4 recorded in the TCGA cancer database, our findings reveal a critical regulatory signaling pathway that suppresses LUAD progression and augments chemotherapy efficacy.

Macrophages play central role in driving airway inflammation during asthma pathogenesis, though the molecular mechanism governing their function remains incompletely understood. Here, we demonstrate that lysine acetyltransferase 8 (KAT8) plays a critical role in papain-induced neutrophilic airway inflammation through post-translational modification of poly(C)-binding protein 1 (PCBP1). We show that papain exposure significantly upregulates KAT8 expression in lung macrophages both in vivo and in vitro. Myeloid-specific Kat8 deficiency conferred protection against papain-induced airway inflammation, reducing CXCL1 and CXCL2 production and consequent neutrophil recruitment. Mechanistically, KAT8 interacted with PCBP1 via its C2HC zinc finger domain and acetylated it at lysine 119 (K119), an essential modification for CXCL1 and CXCL2 secretion. Moreover, KAT8 enhanced M1 macrophage polarization in papain-exposed mice. Importantly, pharmacological inhibition of KAT8 significantly attenuated neutrophil infiltration and allergic airway inflammation in vivo. Our findings establish KAT8 as a pivotal regulator of neutrophilic airway inflammation through PCBP1 acetylation and highlight the KAT8-PCBP1 axis as a promising therapeutic target for severe asthma.

Exposure to fine particulate matter (PM2.5) represents a leading environmental cause of pulmonary inflammation and diseases, yet the underlying cellular mechanisms remain incompletely understood. Here, we identify histone deacetylase 10 (HDAC10) in macrophages as a critical regulator of PM2.5-induced airway inflammation by governing autophagic flux. PM2.5 exposure upregulated HDAC10 expression specifically in lung macrophages both in vivo and in vitro. Myeloid-specific Hdac10 deletion markedly attenuated PM2.5-induced airway inflammation and inflammatory cytokine production by inhibiting macrophage autophagy. Mechanistically, HDAC10 interacted with Beclin1 and deacetylated it at lysine 5 (K5), a modification critical for autophagic flux and subsequent inflammatory responses. Pharmacological inhibition of HDAC10 with salvianolic acid B reduced Beclin1 deacetylation, suppressed macrophage autophagy, and ameliorated PM2.5-induced lung inflammation. Clinically, elevated HDAC10 expression and reduced Beclin1 acetylation were observed in lung tissues from chronic obstructive pulmonary disease (COPD) patients, where HDAC10 mRNA levels correlated positively with the heightened lung inflammation. Our findings reveal a previously unrecognized HDAC10-Beclin1 axis that links PM2.5 exposure to macrophage autophagy and pulmonary inflammation, providing potential therapeutic targets for PM2.5-related respiratory diseases.

Abstract Background The advent of immunotherapy targeting immune checkpoints has conferred significant clinical advantages to patients with lung adenocarcinoma (LUAD); However, only a limited subset of patients exhibit responsiveness to this treatment. Consequently, there is an imperative need to stratify LUAD patients based on their response to immunotherapy and enhance the therapeutic efficacy of these treatments. Methods The differentially co-expressed genes associated with CD8 + T cells were identified through weighted gene co-expression network analysis (WGCNA) and the Search Tool for the Retrieval of Interacting Genes (STRING) database. These gene signatures facilitated consensus clustering for TCGA-LUAD and GEO cohorts, categorizing them into distinct immune subtypes (C1, C2, C3, and C4). The Tumor Immune Dysfunction and Exclusion (TIDE) model and Immunophenoscore (IPS) analysis were employed to assess the immunotherapy response of these subtypes. Additionally, the impact of inhibitors targeting five hub genes on the interaction between CD8 + T cells and LUAD cells was evaluated using CCK8 and EDU assays. To ascertain the effects of these inhibitors on immune checkpoint genes and the cytotoxicity mediated by CD8 + T cells, flow cytometry, qPCR, and ELISA methods were utilized. Results Among the identified immune subtypes, subtypes C1 and C3 were characterized by an abundance of immune components and enhanced immunogenicity. Notably, both C1 and C3 exhibited higher T cell dysfunction scores and elevated expression of immune checkpoint genes. Multi-cohort analysis of Lung Adenocarcinoma (LUAD) suggested that these subtypes might elicit superior responses to immunotherapy and chemotherapy. In vitro experiments involved co-culturing LUAD cells with CD8 + T cells and implementing the inhibition of five pivotal genes to assess their function. The inhibition of these genes mitigated the immunosuppression on CD8 + T cells, reduced the levels of PD1 and PD-L1, and promoted the secretion of IFN-γ and IL-2. Conclusions Collectively, this study delineated LUAD into four distinct subtypes and identified five hub genes correlated with CD8 + T cell activity. It lays the groundwork for refining personalized therapy and immunotherapy strategies for patients with LUAD.

Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.

Introduction: Chronic obstructive pulmonary disease (COPD), an incurable chronic respiratory disease, has become a major public health problem. The relationship between the composition of intestinal microbiota and the important clinical factors affecting COPD remains unclear. This study aimed to identify specific intestinal microbiota with high clinical diagnostic value for COPD. Methods: The fecal microbiota of patients with COPD and healthy individuals were analyzed by 16S rDNA sequencing. Random forest classification was performed to analyze the different intestinal microbiota. Spearman correlation was conducted to analyze the correlation between different intestinal microbiota and clinical characteristics. A microbiota-disease network diagram was constructed using the gut MDisorder database to identify the possible pathogenesis of intestinal microorganisms affecting COPD, screen for potential treatment, and guide future research. Results: No significant difference in biodiversity was shown between the two groups but significant differences in microbial community structure. Fifteen genera of bacteria with large abundance differences were identified, including Bacteroides, Prevotella, Lachnospira, and Parabacteroides. Among them, the relative abundance of Lachnospira and Coprococcus was negatively related to the smoking index and positively related to lung function results. By contrast, the relative abundance of Parabacteroides was positively correlated with the smoking index and negatively correlated with lung function findings. Random forest classification showed that Lachnospira was the genus most capable of distinguishing between patients with COPD and healthy individuals suggesting it may be a potential biomarker of COPD. A Lachnospira disease network diagram suggested that Lachnospira decreased in some diseases, such as asthma, diabetes mellitus, and coronavirus disease 2019 (COVID-19), and increased in other diseases, such as irritable bowel syndrome, hypertension, and bovine lichen. Conclusion: The dominant intestinal microbiota with significant differences is related to the clinical characteristics of COPD, and the Lachnospira has the potential value to identify COPD.

Background Aberrant activation of macrophages is associated with pathogenesis of acute lung injury (ALI). However, the potential pathogenesis has not been explored. Objectives We aimed to identify whether histone deacetylase (HDAC) 10 is involved in lipopolysaccharide (LPS)-exposed ALI and reveal the underlying pathogenesis by which it promotes lung inflammation in LPS-exposed ALI via modifying P62 with deacetylation. Methods We constructed an ALI mice model stimulated with LPS to determine the positive effect of Hdac10 deficiency. Moreover, we cultured murine alveolar macrophage cell line (MH-S cells) and primary bone marrow-derived macrophages (BMDMs) to explore the pro-inflammatory activity and mechanism of HDAC10 after LPS challenge. Results HDAC10 expression was increased both in mice lung tissues and macrophage cell lines and promoted inflammatory cytokines production exposed to LPS. Hdac10 deficiency inhibited autophagy and inflammatory response after LPS stimulation. In vivo, Hdac10(fl/fl)-LysMCre mice considerably attenuated lung inflammation and inflammatory cytokines release exposed to LPS. Mechanistically, HDAC10 interacts with P62 and mediates P62 deacetylation at lysine 165 (K165), by which it promotes P62 expression and increases inflammatory cytokines production. Importantly, we identified that Salvianolic acid B (SAB), an HDAC10 inhibitor, reduces lung inflammatory response in LPS-stimulated ALI. Conclusion These results uncover a previously unknown role for HDAC10 in regulating P62 deacetylation and aggravating lung inflammation in LPS-induced ALI, implicating that targeting HDAC10 is an effective therapy for LPS-exposed ALI.

N6-methyladenosine (m6A) modification accounts for the most prevalent mRNA internal modification and has emerged as a widespread regulatory mechanism in multiple physiological processes. We address a role of methyltransferase-like protein 3 (METTL3) in neutrophil activation. METTL3 controls neutrophil release from bone marrow to circulation through surface expression of CXC chemokine receptor 2 (CXCR2) in a Toll-like receptor 4 (TLR4) signaling-dependent manner in lipopolysaccharide (LPS)-induced endotoxemia. We show that the mRNA of TLR4 is modified by m6A, exhibiting increased translation and slowed degradation simultaneously, leading to elevated protein levels of TLR4, which eventually promotes the TLR4 signaling activation of neutrophil. The reduced expression of TLR4 lowers cytokine secretion in METTL3-deleted neutrophils upon LPS stimulation through TLR4/Myd88/nuclear factor κB (NF-κB) signaling. Collectively, these data demonstrate that METTL3 modulation of TLR4 expression is a critical determinant of neutrophil activation in endotoxemia.

Steroid resistance represents a major clinical problem in the treatment of severe asthma, and therefore a better understanding of its pathogenesis is warranted. Recent studies indicated that histone deacetylase 2 (HDAC2) and interleukin 17A (IL-17A) play important roles in severe asthma. HDAC2 activity is reduced in patients with severe asthma and smoking-induced asthma, perhaps accounting for the amplified expression of inflammatory genes, which is associated with increased acetylation of glucocorticoid receptors. Neutrophilic inflammation contributes to severe asthma and may be related to T helper (Th) 17 rather than Th2 cytokines. IL-17A levels are elevated in severe asthma and correlate with the presence of neutrophils. Restoring the activity of HDAC2 or targeting the Th17 signaling pathway is a potential therapeutic approach to reverse steroid insensitivity.

Purpose: Particulate matter (PM2.5) is a common risk factor for airway inflammation. Alveolar macrophages play a critical role in airway inflammation. Sirtuin 6 (SIRT6) is a class Ill histone deacetylase that exerts an anti-inflammatory effect in airway diseases. However, the role of SIRT6 on PM2.5-induced airway inflammation in macrophages remains unclear. We aimed to determine whether SIRT6 protects against PM2.5-induced airway inflammation in macrophages. Methods: The effect of SIRT6 on PM2.5-induced airway inflammation was assessed by using THP1 cells or bone marrow-derived macrophages (BMDMs) exposed to PM2.5 in vitro and myeloid cell-specific SIRT6 conditional knockout mice (Sirt6fl/fl-LysMCre) in vivo. Results: PM2.5 increased SIRT6 expression in THP1 cells, but SIRT6 gene silencing decreased PM2.5 induced inflammatory cytokines in THP1 cells. Moreover, the expression of SIRT6 and inflammatory cytokines was also decreased in BMDMs with myeloid-specific deletion of SIRT6 after stimulation of PM2.5. In vivo, Sirt6fl/fl-LysMCre mice substantially decreased airway inflammation in response to PM2.5 exposure. Conclusion: Our results revealed that SIRT6 promotes the PM2.5-induced airway inflammation in macrophages and indicated that inhibition of SIRT6 in macrophages may represent therapeutic strategy for airway disorders induced by airborne particulate pollution.

Background: Perturbation of macrophage homeostasis is one of the key mechanisms of airway inflammation in asthma. However, the exact mechanisms remain poorly understood. Objectives: We sought to examine the role of histone deacetylase (HDAC) 10 as an epigenetic regulator that governs macrophage M2 program and promotes airway inflammation in asthma, and to elucidate the underlying mechanisms. Methods: Peripheral blood and airway biopsies were obtained from healthy individuals and asthmatic patients. Asthma was induced by exposure to allergen in mice with myeloid-specific deletion of Hdac10 (Hdac10fl/fl-LysMCre) mice. HDAC10 inhibitor Salvianolic acid B (SAB), STAT3 selective agonist Colivelin, and the specific PI3K/Akt activator 1,3-Dicaffeoylquinic acid (DA) were also used in asthmatic mice. For cell studies, THP1 cells, primary mouse bone marrow derived macrophage (BMDMs) were used and related signaling pathways was investigated. Results: HDAC10 expression was highly expressed by macrophages and promoted M2 macrophage activation and airway inflammation in asthmatic patients and mice. Hdac10fl/fl-LysMCre mice were protected from airway inflammation in experimental asthma model. Hdac10 deficiency significantly attenuated STAT3 expression and decreased M2 macrophage polarization following allergen exposure. Mechanistically, HDAC10 directly binds STAT3 for deacetylation in macrophages, by which it promotes STAT3 expression and activates the macrophage M2 program. Importantly, we identified SAB as a HDAC10 inhibitor that had protective effects against airway inflammation in mice. Conclusions: Our results revealed that HDAC10-STAT3 interaction governs macrophage polarization to promote airway inflammation in asthma, implicating HDAC10 as a therapeutic target.

Asthma is a complex chronic airway inflammatory disease that seriously impacts patients' quality of life. As a novel approach to exploring the pathogenesis of diseases, metabolomics provides the potential to identify biomarkers of asthma host susceptibility and elucidate biological pathways. The aim of this study was to screen potential biomarkers and biological pathways so as to provide possible pharmacological therapeutic targets for asthma. In the present study, we merged the differentially expressed genes (DEGs) of asthma in the GEO database with the metabolic genes obtained by Genecard for bioinformatics analysis and successfully screened out the metabolism-related hub genes (HIF1A, OCRL, NNMT, and PER1). Then, untargeted metabolic techniques were utilized to reveal HDM-induced metabolite alterations in 16HBE cells. A total of 45 significant differential metabolites and 5 differential metabolic pathways between the control group and HDM group were identified based on the OPLS-DA model. Finally, three key metabolic pathways, including glycerophospholipid metabolism, galactose metabolism, and alanine, aspartate, and glutamate metabolism, were screened through the integrated analysis of bioinformatics data and untargeted metabolomics data. Taken together, these findings provide valuable insights into the pathophysiology and targeted therapy of asthma and lay a foundation for further research.

Dysregulation of IL-17A is closely associated with airway inflammation and remodeling in severe asthma. However, the molecular mechanisms by which IL-17A is regulated remain unclear. Here we identify epithelial sirtuin 6 (SIRT6) as an epigenetic regulator that governs IL-17A pathogenicity in severe asthma. Mice with airway epithelial cell-specific deletion of Sirt6 are protected against allergen-induced airway inflammation and remodeling via inhibiting IL-17A-mediated inflammatory chemokines and mesenchymal reprogramming. Mechanistically, SIRT6 directly interacts with RORγt and mediates RORγt deacetylation at lysine 192 via its PPXY motifs. SIRT6 promotes RORγt recruitment to the IL-17A gene promoter and enhances its transcription. In severe asthma patients, high expression of SIRT6 positively correlates with airway remodeling and disease severity. SIRT6 inhibitor (OSS_128167) treatment significantly attenuates airway inflammation and remodeling in mice. Collectively, these results uncover a function for SIRT6 in regulating IL-17A pathogenicity in severe asthma, implicating SIRT6 as a potential therapeutic target for severe asthma.

哮喘主要以气道炎症、气道重塑和气道高反应性为特征,其分子机制未明.蛋白质翻译后修饰是指以共价方式在氨基酸残基上加上或去除修饰基团,进而调节蛋白功能,主要包括磷酸化、乙酰化、泛素化、糖基化、脂质化、亚硝基化和蛋白水解等.该文总结了蛋白质翻译后修饰在哮喘发病机制中的研究进展,提出现存问题及展望.