Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI3K/Akt1 pathway

• Published in: Immunology 2018-11, Vol.155 (3), p.387-395
• Main Authors: Zhao, Hang, Ma, Yating, Zhang, Leifang
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT1 protein; Alveoli; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - immunology; Bronchus; Caspase; Cell activation; Cell differentiation; Clonal deletion; Differentiation (biology); Hyaluronic acid; Hyaluronic Acid - pharmacology; Hyaluronic Acid - toxicity; Inflammation; Inflammation - chemically induced; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Inflammatory diseases; Inflammatory response; Interleukins; Kinases; Leukemia; low‐molecular‐weight hyaluronan (200 000 MW); Lung - immunology; Lung - pathology; Lung diseases; lung inflammation; Lungs; Matrix metalloproteinase; Mcl‐1; Medical treatment; Metalloproteinase; Mice; Mice, Knockout; Molecular weight; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - immunology; neutrophil; Neutrophils; Neutrophils - immunology; Neutrophils - pathology; Original; Pharmacology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - immunology; phosphoinositide 3‐kinase/Akt1; Pneumonia - chemically induced; Pneumonia - genetics; Pneumonia - immunology; Pneumonia - pathology; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - immunology; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Signaling; Trachea; Up-Regulation - drug effects; Up-Regulation - immunology
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12981

Summary Although low‐molecular‐mass hyaluronan (LMMHA) has been implicated in pulmonary inflammatory diseases, the signalling pathway of LMMHA (200 000 molecular weight) that initiates the inflammatory response in lung is still unknown. In this study, we evaluate the role of phosphoinositide 3‐kinase (PI3K) and its downstream signalling pathway in LMMHA‐induced lung inflammatory responses. Our results indicate that pharmacological inhibition of PI3K or genetic deletion of Akt1 enhances neutrophil apoptosis, attenuates neutrophil influx into the lungs of mice and diminishes the expression of pro‐inflammatory factors such as interleukin‐6, keratinocyte cell‐derived chemokine and pro‐matrix metalloproteinase‐9 in bronchoalveolar lavage fluid after intratracheal administration of LMMHA. More importantly, we found that PI3K/Akt1 participates in LMMHA‐induced inflammatory responses, which are mainly mediated by the myeloid leukaemia cell differentiation protein (Mcl‐1). Our study suggests that LMMHA induced significantly increased levels of inflammatory factors in bronchoalveolar lavage fluid and activation of the PI3K/Akt1 pathway, which up‐regulates the expression of the anti‐apoptotic protein Mcl‐1 and inhibits the activation of caspase‐3, thereby suppressing neutrophil apoptosis to trigger lung inflammation. These findings reveal a novel molecular mechanism underlying sterile inflammation and provides a new potential target for the treatment of pulmonary disease. Low‐molecular‐mass hyaluronan (LMMHA; 200 000 MW) is a critical signal in neutrophil activation and recruitment, leading to lung inflammation. Our study indicates that LMMHA induced activation of the PI3K/Akt1 pathway, which up‐regulates the expression of the anti‐apoptotic protein Mcl‐1 to delay lung neutrophil apoptosis. Hence, inhibition of the PI3K/Akt1 pathway exerts a protective role in LMMHA‐induced lung inflammation.