A proinflammatory long noncoding RNA Lncenc1 regulates inflammasome activation in macrophage.

Mammalian genomes encode thousands of long noncoding RNAs (lncRNAs). LncRNAs are extensively expressed in various immune cells. The lncRNAs have been reported to be involved in diverse biological processes, including the regulation of gene expression, dosage compensation, and genomic imprinting. However, very little research has been conducted to explore how they alter innate immune responses during host-pathogen interactions. In this study, we found that a lncRNA, named long noncoding RNA, embryonic stem cells expressed 1 (Lncenc1), was strikingly increased in mouse lungs after gram-negative (G-) bacterial infection or exposure to lipopolysaccharides (LPS). Interestingly, our data indicated that Lncenc1 was upregulated in macrophages but not in primary epithelial cells (PECs) or polymorphonuclear leukocytes (PMN). The upregulation was also observed in human THP-1 and U937 macrophages. Besides, Lncenc1 was highly induced during ATP-induced inflammasome activation. Functionally, Lncenc1 showed proinflammatory effects in macrophages as demonstrated by increased expressions of cytokine and chemokines, as well as enhanced NF-κB promoter activity. Overexpression of Lncenc1 promoted the releases of IL-1ß and IL-18, and Caspase-1 activity in macrophages, suggesting a role in inflammasome activation. Consistently, knockdown of Lncenc1 inhibited inflammasome activation in LPS-treated macrophages. Moreover, knockdown of Lncenc1 using antisense oligo (ASO)-loaded exosomes (EXO) attenuated LPS-induced lung inflammation in mice. Similarly, Lncenc1 deficiency protects mice from bacteria-induced lung injury and inflammasome activation. Taken together, our work identified Lncenc1 as a modulator of inflammasome activation in macrophages during bacterial infection. Our study suggested that Lncenc1 could serve as a therapeutic target for lung inflammation and injury.

TIMP-1 and its potential diagnostic and prognostic value in pulmonary diseases.

Tissue inhibitors of metalloproteases (TIMPs) have caught the attention of many scientists due to their role in various physiological and pathological processes. TIMP-1, 2, 3, and 4 are known members of the TIMPs family. TIMPs exert their biological effects by, but are not limited to, inhibiting the activity of metalloproteases (MMPs). The balance between MMPs and TIMPs is critical for maintaining homeostasis of the extracellular matrix (ECM), while the imbalance between MMPs and TIMPs can lead to pathological changes, such as cancer. In this review, we summarized the current knowledge of TIMP-1 in several pulmonary diseases namely, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), pneumonia, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and pulmonary fibrosis. Considering the potential of TIMP-1 serving as a non-invasive diagnostic and/or prognostic biomarker, we also reviewed the circulating TIMP-1 levels in translational and clinical studies.

Dysregulation of miR-103a Mediates Cigarette Smoking-induced Lipid-laden Macrophage Formation.

Cigarette smoke (CS) is considered a major risk factor for chronic obstructive pulmonary disease (COPD) that is currently the third leading cause of death in the United States. Studies have indicated that patients with COPD have elevated blood low-density lipoprotein levels, which may contribute to the dysregulation of lipid metabolism. Accumulating data show that microRNAs (miRNAs) are involved in various human diseases. However, the role of microRNAs in the pathogenesis of COPD remains poorly defined. In this study, we found that miR-103a expression was significantly reduced in alveolar macrophages from smokers and patients with COPD versus that in alveolar macrophages from nonsmokers. Our data indicated that reactive oxygen species negatively regulate miR-103a in macrophages. Functionally, miR-103a modulates the expressions of genes involved in lipid metabolism and directly targets low-density lipoprotein receptors in macrophages. Furthermore, overexpression of miR-103a suppressed the accumulation of lipid droplets and reduced the reactive oxygen species, both in vitro and in vivo. Taken together, our findings indicate that downregulation of miR-103a contributes to cigarette smoke-induced lipid-laden macrophage formation and plays a critical role in lipid homeostasis in lung macrophages in the pathogenesis of COPD.

CC16 Regulates Inflammation, ROS Generation and Apoptosis in Bronchial Epithelial Cells during Klebsiella pneumoniae Infection.

Gram-negative (G-) bacteria are the leading cause of hospital-acquired pneumonia in the United States. The devastating damage caused by G- bacteria results from the imbalance of bactericidal effects and overwhelming inflammation. Despite decades of research, the underlying mechanisms by which runaway inflammation is developed remain incompletely understood. Clara Cell Protein 16 (CC16), also known as uteroglobin, is the major protein secreted by Clara cells and the most abundant protein in bronchoalveolar lavage fluid (BALF). However, the regulation and functions of CC16 during G- bacterial infection are unknown. In this study, we aimed to assess the regulation of CC16 in response to Klebsiella pneumoniae (K. pneu) and to investigate the role of CC16 in bronchial epithelial cells. After K. pneu infection, we found that CC16 mRNA expression was significantly decreased in bronchial epithelial cells. Our data also showed that K. pneu infection upregulated cytokine and chemokine genes, including IL-1ß, IL-6, and IL-8 in BEAS-2B cells. Endogenously overexpressed CC16 in BEAS-2B cells provided an anti-inflammatory effect by reducing these markers. We also observed that endogenous CC16 can repress NF-κB reporter activity. In contrast, the recombinant CC16 (rCC16) did not show an anti-inflammatory effect in K. pneu-infected cells or suppression of NF-κB promoter activity. Moreover, the overexpression of CC16 reduced reactive oxygen species (ROS) levels and protected BEAS-2B cells from K. pneu-induced apoptosis.

Club Cell Secreted Protein CC16: Potential Applications in Prognosis and Therapy for Pulmonary Diseases.

Club cell secretory protein (CC16) is encoded by the SCGB1A1 gene. It is also known as CC10, secretoglobin, or uteroglobin. CC16 is a 16 kDa homodimeric protein secreted primarily by the non-ciliated bronchial epithelial cells, which can be detected in the airways, circulation, sputum, nasal fluid, and urine. The biological activities of CC16 and its pathways have not been completely understood, but many studies suggest that CC16 has anti-inflammatory and anti-oxidative effects. The human CC16 gene is located on chromosome 11, p12-q13, where several regulatory genes of allergy and inflammation exist. Studies reveal that factors such as gender, age, obesity, renal function, diurnal variation, and exercise regulate CC16 levels in circulation. Current findings indicate CC16 not only may reflect the pathogenesis of pulmonary diseases, but also could serve as a potential biomarker in several lung diseases and a promising treatment for chronic obstructive pulmonary disease (COPD). In this review, we summarize our current understanding of CC16 in pulmonary diseases.

The Roles of CCN1/CYR61 in Pulmonary Diseases.

CCN1 (cysteine-rich 61, connective tissue growth factor, and nephroblastoma-1), previously named CYR61 (cysteine-rich angiogenic inducer 61) belongs to the CCN family of matricellular proteins. CCN1 plays critical roles in the regulation of proliferation, differentiation, apoptosis, angiogenesis, and fibrosis. Recent studies have extensively characterized the important physiological and pathological roles of CCN1 in various tissues and organs. In this review, we summarize both basic and clinical aspects of CCN1 in pulmonary diseases, including acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), lung fibrosis, pulmonary arterial hypertension (PAH), lung infection, and lung cancer. We also emphasize the important challenges for future investigations to better understand the CCN1 and its role in physiology and pathology, as well as the questions that need to be addressed for the therapeutic development of CCN1 antagonists in various lung diseases.