Macrophage Extracellular Traps Suppress Particulate Matter-Induced Airway Inflammation.

Accumulating evidence has substantiated the potential of ambient particulate matter (PM) to elicit detrimental health consequences in the respiratory system, notably airway inflammation. Macrophages, a pivotal component of the innate immune system, assume a crucial function in responding to exogenous agents. However, the roles and detailed mechanisms in regulating PM-induced airway inflammation remain unclear. Our study revealed that PM had the ability to stimulate the formation of macrophage extracellular traps (METs) both in vitro and in vivo. This effect was found to be dependent on peptidylarginine deiminase type 4 (PAD4)-mediated histone citrullination. Additionally, reactive oxygen species were also found to be involved in the formation of PM-induced METs, in parallel with PAD4. Genetic deletion of PAD4 in macrophages resulted in an up-regulation of inflammatory cytokine expression. Moreover, mice with PAD4-specific knockout in myeloid cells exhibited exacerbated PM-induced airway inflammation. Mechanistically, inhibition of METs suppressed the phagocytic ability in macrophages, leading to airway epithelial injuries and an aggravated PM-induced airway inflammation. The present study demonstrates that METs play a crucial role in promoting the phagocytosis and clearance of PM by macrophages, thereby suppressing airway inflammation. Furthermore, it suggests that activation of METs may represent a novel therapeutic strategy for PM-related airway disorders.

Rapamycin Exacerbates Staphylococcus aureus Pneumonia by Inhibiting mTOR-RPS6 in Macrophages.

Purpose: This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism. Methods: We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models. Results: Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia. Conclusion: Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.

Airway epithelial cGAS inhibits LPS-induced acute lung injury through CREB signaling.

Increased levels of cytosolic DNA in lung tissues play an important role in acute lung injury. However, the detailed mechanisms involved remain elusive. Here, we found that cyclic GMP-AMP synthase (cGAS, a cytosolic DNA sensor) expression was increased in airway epithelium in response to increased cytosolic DNA. Conditional deletion of airway epithelial cGAS exacerbated acute lung injury in mice, cGAS knockdown augmented LPS-induced production of interleukin (IL)-6 and IL-8. Mechanically, deletion of cGAS augmented expression of phosphorylated CREB (cAMP response element-binding protein), and cGAS directly interacted with CREB via its C-terminal domain. Furthermore, CREB knockdown rescued the LPS-induced excessive inflammatory response caused by cGAS deletion. Our study demonstrates that airway epithelial cGAS plays a protective role in acute lung injury and confirms a non-canonical cGAS-CREB pathway that regulates the inflammatory responses in airway epithelium to mediate LPS-induced acute lung injury.

The Scap-SREBP1-S1P/S2P lipogenesis signal orchestrates the homeostasis and spatiotemporal activation of NF-κB.

The nuclear factor κB (NF-κB) pathway plays essential roles in innate and adaptive immunity, but little is known how NF-κB signaling is compartmentalized and spatiotemporally activated in the cytoplasm. Here, we show that the lipogenesis signal cascade Scap-SREBP1-S1P/S2P orchestrates the homeostasis and spatiotemporal activation of NF-κB. SREBP cleavage-activating protein (Scap) and sterol regulatory element-binding protein 1 (SREBP1) form a super complex with inhibitors of NF-κB α (IκBα) to associate NF-κB close to the endoplasmic reticulum (ER). Upon lipopolysaccharide (LPS) stimulation, Scap transports the complex to the Golgi apparatus, where SREBP1 is cleaved by site-1 protease (S1P)/S2P, liberating IκBα for IκB kinase (Ikk)-mediated phosphorylation and subsequent activation of NF-κB. Loss of Scap or inhibition of S1P or S2P diminishes, while SREBP1 deficiency augments, LPS-induced NF-κB activation and subsequent inflammatory responses. Our results reveal the Scap-SREBP1 complex as an additional cytoplasmic checkpoint for NF-κB homeostasis and unveil the Golgi apparatus as the optimal cellular platform for NF-κB activation, providing insights into the crosstalk between lipogenesis signaling and immunity.

PRAME Is a Potential Carcinogenic Biomarker that Correlates with Patient Prognosis and Tumor Immunity Based on Pan-Cancer Analysis.

OBJECTIVE: This study was designed to visualize the pan-cancer prognostic significance of PReferentially expressed Antigen in Melanoma (PRAME) and investigate the relationship between PRAME expression and tumor immunity. MATERIAL AND METHODS: We explored the expression patterns and prognostic value of PRAME across multiple cancers using data from the Cancer Genome Atlas, Genotype-Tissue Expression, and Cancer Cell Line Encyclopedia databases. Spearman's correlation test was used to evaluate correlations between PRAME expression and the tumor immune microenvironment, mutation indicators, and DNA methylation. Finally, the functions of PRAME and potential signaling pathway mechanisms were explored through Gene Set Enrichment Analysis (GSEA). RESULTS: Pan-cancer survival analysis indicated that PRAME was widely up-regulated in most tumors, and its high expression was indicative of poor overall survival in different cancer types. In addition, PRAME expression levels were strongly linked to immune infiltration, immune score, immune checkpoint, immune neoantigens, tumor mutation burden, microsatellite instability, mismatch repair, and DNA methyltransferase in a variety of cancers. GSEA analysis revealed that PRAME was related to the regulation of numerous signaling pathways implicated in tumor immunity and tumorigenicity. CONCLUSIONS: PRAME has the potential to serve as a prognostic pan-cancer biomarker and is correlated with tumor immunity. Its use may help shed light on optimum cancer therapies.

A Spontaneous H2-Aa Point Mutation Impairs MHC II Synthesis and CD4+ T-Cell Development in Mice.

Major histocompatibility complex class II (MHC II) is an essential immune regulatory molecule that plays an important role in antigen presentation and T-cell development. Abnormal MHC II expression can lead to immunodeficiency, clinically termed as type II bare lymphocyte syndrome (BLS), which usually results from mutations in the MHC II transactivator (CIITA) and other coactivators. Here, we present a new paradigm for MHC II deficiency in mice that involves a spontaneous point mutation on H2-Aa. A significantly reduced population of CD4+ T cells was observed in mice obtained from the long-term homozygous breeding of autophagy-related gene microtubule-associated protein 1 light chain 3 ß (Map1lc3b, Lc3b) knockout mice; this phenotype was not attributed to the original knocked-out gene. MHC II expression was generally reduced, together with a marked deficiency of H2-Aa in the immune cells of these mice. Using cDNA and DNA sequencing, a spontaneous H2-Aa point mutation that led to false pre-mRNA splicing, deletion of eight bases in the mRNA, and protein frameshift was identified in these mice. These findings led to the discovery of a new type of spontaneous MHC II deficiency and provided a new paradigm to explain type II BLS in mice.

miRNA-93-5p Promotes Gemcitabine Resistance in Pancreatic Cancer Cells by Targeting the PTEN-Mediated PI3K/Akt Signaling Pathway.

OBJECTIVE: To investigate the role and potential underlying mechanism of miR-93-5p in the carcinogenesis and gemcitabine resistance of pancreatic cancer (PC) cells. METHODS: We generated a gemcitabine-resistant PC cell line Bxpc-3/GemR following prolonged gemcitabine exposure to its parental gemcitabine-sensitive counterpart Bxpc-3/Par. Cell viability was monitored by MTS assay. Transfection was performed using Lipofectamine 3000 reagent. Cell apoptosis and rhodamine 123 fluorescence were detected by flow cytometry. Luciferase activities were measured using the luciferase reporter gene assay. Expression analysis was carried out by qRT-PCR and western blot. RESULTS: Significantly increased viability and enhanced expression of the multi-drug resistance-1 (MDR1) gene were observed in Bxpc-3/GemR cells, in which miR-93-5p is considerably upregulated, compared with Bxpc-3/Par cells. Downregulation of miR-93-5p inhibited cell viability, induced cell apoptosis, and decreased MDR1 expression in Bxpc-3/GemR cells, whereas upregulation essentially reversed these properties in Bxpc-3/Par cells. We further confirmed that PTEN was a direct target of miR-93-5p, and overexpression of miR-93-5p was accompanied by a significant increase in the phosphorylation of Akt expression in the Bxpc-3/Par cells. Moreover, inhibition of PI3K/Akt signaling diminished MDR1 expression. CONCLUSION: These observations suggest that miR-93-5p modulates tumorigenesis and gemcitabine resistance in PC cells via targeting the PTEN/PI3K/Akt signaling pathway.

Epithelium-derived IL17A Promotes Cigarette Smoke-induced Inflammation and Mucus Hyperproduction.

The airway epithelium is a central modulator of innate and adaptive immunity in the lung. IL17A expression was found to be increased in the airway epithelium; however, the role of epithelium-derived IL17A in chronic obstructive pulmonary disease (COPD) remains unclear. In this study, we aimed to determine whether epithelium-derived IL17A regulates inflammation and mucus hyperproduction in COPD by using a cultured human bronchial epithelial (HBE) cell line in vitro and an airway epithelium IL17A-specific knockout mouse in vivo. Increased IL17A expression was observed in the mouse airway epithelium upon cigarette smoke (CS) exposure or in a mouse model of COPD that was induced by using CS and Eln (elastin). CS extract (CSE) also triggered IL17A expression in HBE cells. Blocking IL17A or IL17RA (IL17 receptor A) effectively attenuated CSE-induced MUC5AC and the inflammatory cytokines IL6, TNF-α, and IL1ß in HBE cells, suggesting that IL17A mediates CSE-induced inflammation and mucin production in an autocrine manner. CSE activated p-JUN (phospho-JUN) and p-JNK (phospho-c-Jun N-terminal kinase), which were also reduced by IL17RA siRNA, and JUN siRNA attenuated CSE-induced IL6 and MUC5AC. In vivo, selective knockout of IL17A in the airway epithelium markedly reduced the neutrophilic infiltration in BAL fluid, peribronchial inflammation, proinflammatory mediators (CXCL1 [CXC ligand 1] and CXCL2), and mucus production in a COPD mouse model. We showed a novel function of airway epithelium-derived IL17A, which can act locally in an autocrine manner to amplify inflammation and increase mucus production in COPD pathogenesis.

Lipid metabolism in asthma: Immune regulation and potential therapeutic target.

Asthma is a chronic inflammatory disease of the lungs that poses a considerable health and socioeconomic burden. Several risk factors work synergistically to affect the progression of asthma. Lipid metabolism, especially in distinct cells such as T cells, macrophages, granulocytes, and non-immune cells, plays an essential role in the pathogenesis of asthma, as lipids are potent signaling molecules that regulate a multitude of cellular response. In this review, we focused on the metabolic pathways of lipid molecules, especially fatty acids and their derivatives, and summarized their roles in various cells during the pathogenesis of asthma along with the current pharmacological agents targeting lipid metabolism.

Prenatal and postnatal exposure to Bisphenol A and Asthma: a systemic review and meta-analysis.

BACKGROUND: Bisphenol A (BPA) is a plasticizer with high production and ubiquitous usage in polycarbonate plastics and epoxy resins. The association between prenatal or postnatal exposure to BPA and childhood wheeze/asthma has not been well established. Our study aimed to provide further justification for the current studies. METHODS: Studies were searched from PubMed, Web of Science, Scopus and Embase from inception until Sep 15, 2020. Meta-analysis was performed to calculate pooled adjusted odds ratios (aOR). The methodological quality of included studies was assessed by using the Newcastle Ottawa Scale (NOS). RESULTS: Of 2,814 screened articles, 9 studies with 3,885 participants were included in the final analysis. When all studies were pooled, postnatal exposure to BPA was associated with a higher risk of childhood asthma (aOR =1.43; 95% CI: 1.28-1.59) or childhood wheeze (aOR =1.38; 95% CI: 1.18-1.62). Prenatal exposure to BPA had a small but significant increased risk of childhood asthma (aOR =1.17; 95% CI: 1.01-1.34). An increased risk of childhood wheeze was related to prenatal exposure to BPA at 16 weeks' gestation (aOR =1.29; 95% CI: 1.07-1.55), but not at 26 weeks' gestation (aOR =1.07; 95% CI: 0.88-1.29) nor at random-time gestation (aOR =1.02; 95% CI: 0.89-1.16). CONCLUSIONS: Prenatal and postnatal exposure to BPA was related to an increased risk of childhood asthma. However, only postnatal and early gestational exposure (at 16 weeks) to BPA could induce the risk of childhood wheeze, but not late gestational exposure (at 26 weeks).

MTOR suppresses autophagy-mediated production of IL25 in allergic airway inflammation.

INTRODUCTION: Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)-autophagy axis in airway epithelial injury in asthma. METHODS: We examined the MTOR-autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related lc3b-/- mice were used for allergic models. RESULTS: MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in lc3b-/- mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice. CONCLUSION: Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma.

SETD8C302R Mutation Revealed from Myofibroblastoma-Discordant Monozygotic Twins Leads to p53/p21 Deficit and WEE1 Inhibitor Sensitivity.

High-throughput gene sequencing has identified various genetic variants as the culprits for some common hereditary cancers. However, the heritability of a substantial proportion of cancers remains unexplained, which may result from rare deleterious mutations hidden in a myriad of nonsense genetic variations. This poses a great challenge to the understanding of the pathology and thus the rational design of effective treatments for affected patients. Here, whole genome sequencing is employed in a representative case in which one monozygotic twin is discordant for lung inflammatory myofibroblastoma to disclose rare tumor-related mutations. A missense single nucleotide variation rs61955126 T>C in the lysine methyltransferase SETD8 (accession: NM_020382, SETD8C302R ) is exposed. It is shown that SETD8 is vital for genomic integrity by promoting faithful DNA replication, and its C302R mutation downregulates the p53/p21 pathway. Importantly, the SETD8C302R mutation significantly increases the sensitivity of cancer cells to WEE1 inhibition. Given that WEE1 inhibitors have shown great promise for clinical approval, these results impart a potential therapeutic approach using WEE1 inhibitor for cancer patients carrying the same mutation, and indicate that genome sequencing and genetic functional studies can be integrated into individualized therapies.

Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation.

INTRODUCTION: Eosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs). METHODS: Eosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation. RESULTS: Treatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo. CONCLUSIONS: FINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.

Homeostatic and early-recruited CD101- eosinophils suppress endotoxin-induced acute lung injury.

INTRODUCTION: Acute lung injury (ALI) is a fatal but undertreated condition with severe neutrophilic inflammation, although little is known about the functions of eosinophils in the pathogenesis of ALI. Our objectives were to investigate the roles and molecular mechanisms of eosinophils in ALI. METHODS: Pulmonary eosinophils were identified by flow cytometry. Mice with abundant or deficient eosinophils were used. Cellularity of eosinophils and neutrophils in bronchoalveolar lavage fluid, inflammatory assessment, and survival rate were determined. Human samples were also used for validating experimental results. RESULTS: Blood eosinophils were increased in surviving patients with acute respiratory distress syndrome (ARDS) independent of corticosteroid usage. There existed homeostatic eosinophils in lung parenchyma in mice and these homeostatic eosinophils, originating from the bone marrow, were predominantly CD101-. More CD101- eosinophils could be recruited earlier than lipopolysaccharide (LPS)-initiated neutrophilic inflammation. Loss of eosinophils augmented LPS-induced pulmonary injury. Homeostatic CD101- eosinophils ameliorated, while allergic CD101+ eosinophils exacerbated, the neutrophilic inflammation induced by LPS. Likewise, CD101 expression in eosinophils from ARDS patients did not differ from healthy subjects. Mechanistically, CD101- eosinophils exhibited higher levels of Alox15 and Protectin D1. Administration of Protectin D1 isomer attenuated the neutrophilic inflammation. CONCLUSIONS: Collectively, our findings identify an uncovered function of native CD101- eosinophils in suppressing neutrophilic lung inflammation and suggest a potential therapeutic target for ALI.

Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice.

It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.

Early recruited neutrophils promote asthmatic inflammation exacerbation by release of neutrophil elastase.

Neutrophils can regulate adaptive immune responses and contribute to chronic inflammation including asthma. However, the roles and mechanisms of neutrophils in initiating eosinophilic airway inflammation remain incompletely understood. Neutrophil elastase (NE) is a component of azurophilic granules and a serine protease with potent functions during inflammation. Here, we showed that neutrophils were early recruited at the onset of asthmatic inflammation by related chemokines. Furthermore, neutrophils could capture allergens and release NE to promote neutrophil aggregation at first. Then they prompt eosinophil infiltration and amplify type 2 immune responses in later phases. Also, this process can be rescued by administration of the NE inhibitor (GW311616). Our data collectively indicate that neutrophils could contribute to asthmatic inflammation by releasing NE.

Airway Epithelial cGAS Is Critical for Induction of Experimental Allergic Airway Inflammation.

DNA damage could lead to the accumulation of cytosolic DNA, and the cytosolic DNA-sensing pathway has been implicated in multiple inflammatory diseases. However, the role of cytosolic DNA-sensing pathway in asthma pathogenesis is still unclear. This article explored the role of airway epithelial cyclic GMP-AMP synthase (cGAS), the major sensor of cytosolic dsDNA, in asthma pathogenesis. Cytosolic dsDNA accumulation in airway epithelial cells (ECs) was detected in the setting of allergic inflammation both in vitro and in vivo. Mice with cGAS deletion in airway ECs were used for OVA- or house dust mite (HDM)-induced allergic airway inflammation. Additionally, the effects of cGAS knockdown on IL-33-induced GM-CSF production and the mechanisms by which IL-33 induced cytosolic dsDNA accumulation in human bronchial epithelial (HBE) cells were explored. Increased accumulation of cytosolic dsDNA was observed in airway epithelium of OVA- or HDM-challenged mice and in HBE cells treated with IL-33. Deletion of cGAS in the airway ECs of mice significantly attenuated the allergic airway inflammation induced by OVA or HDM. Mechanistically, cGAS participates in promoting TH2 immunity likely via regulating the production of airway epithelial GM-CSF. Furthermore, Mito-TEMPO could reduce IL-33-induced cytoplasmic dsDNA accumulation in HBE cells possibly through suppressing the release of mitochondrial DNA into the cytosol. In conclusion, airway epithelial cGAS plays an important role via sensing the cytosolic dsDNA in asthma pathogenesis and could serve as a promising therapeutic target against allergic airway inflammation.

Inactivation of MTOR promotes autophagy-mediated epithelial injury in particulate matter-induced airway inflammation.

Particulate matter (PM) is able to induce airway epithelial injury, while the detailed mechanisms remain unclear. Here we demonstrated that PM exposure inactivated MTOR (mechanistic target of rapamycin kinase), enhanced macroautophagy/autophagy, and impaired lysosomal activity in HBE (human bronchial epithelial) cells and in mouse airway epithelium. Genetic or pharmaceutical inhibition of MTOR significantly enhanced, while inhibition of autophagy attenuated, PM-induced IL6 expression in HBE cells. Consistently, club-cell-specific deletion of Mtor aggravated, whereas loss of Atg5 in bronchial epithelium reduced, PM-induced airway inflammation. Interestingly, the augmented inflammatory responses caused by MTOR deficiency were markedly attenuated by blockage of downstream autophagy both in vitro and in vivo. Mechanistically, the dysregulation of MTOR-autophagy signaling was partially dependent on activation of upstream TSC2, and interacted with the TLR4-MYD88 to orchestrate the downstream NFKB activity and to regulate the production of inflammatory cytokines in airway epithelium. Moreover, inhibition of autophagy reduced the expression of EPS15 and the subsequent endocytosis of PM. Taken together, the present study provides a mechanistic explanation for how airway epithelium localized MTOR-autophagy axis regulates PM-induced airway injury, suggesting that activation of MTOR and/or suppression of autophagy in local airway might be effective therapeutic strategies for PM-related airway disorders.Abbreviations: ACTB: actin beta; AKT: AKT serine/threonine kinase; ALI: air liquid interface; AP2: adaptor related protein complex 2; ATG: autophagy related; BALF: bronchoalveolar lavage fluid; COPD: chronic obstructive pulmonary disease; CXCL: C-X-C motif chemokine ligand; DOX: doxycycline; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EPS15: epidermal growth factor receptor pathway substrate 15; HBE: human bronchial epithelial; H&E: hematoxylin & eosin; IKK: IKB kinase; IL: interleukin; LAMP2: lysosomal-associated membrane protein 2; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTEC: mouse tracheal epithelial cells; MTOR: mechanistic target of rapamycin kinase; MYD88: MYD88 innate immune signal transduction adaptor; NFKB: nuclear factor of kappa B; NFKBIA: NFKB inhibitor alpha; PM: particulate matter; PtdIns3K: phosphatidylinositol 3-kinase; Rapa: rapamycin; RELA: RELA proto-oncogene, NFKB subunit; SCGB1A1: secretoglobin family 1A member 1; siRNA: small interfering RNAs; SQSTM1: sequestosome 1; TEM: transmission electronic microscopy; TLR4: toll like receptor 4; TSC2: TSC complex subunit 2.

Lipid metabolism in chronic obstructive pulmonary disease.

Dysregulated lipid metabolism plays crucial roles in various diseases, including diabetes mellitus, cancer, and neurodegeneration. Recent studies suggest that alterations in major lipid metabolic pathways contribute to pathogenesis of lung diseases, including chronic obstructive pulmonary disease (COPD). These changes allow lung tissue to meet the energy needs and trigger anabolic pathways that initiate the synthesis of active molecules directly involved in the inflammation. In this review, we summarize the changes of catabolism and anabolism of lipids, lipid molecules including lipid mediators, lipid synthesis transcription factors, cholesterol, and phospholipids, and how those lipid molecules participate in the initiation and resolution of inflammation in COPD.