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Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI 3K/Akt1 pathway
Author(s) -
Zhao Hang,
Ma Yating,
Zhang Leifang
Publication year - 2018
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12981
Subject(s) - bronchoalveolar lavage , inflammation , pi3k/akt/mtor pathway , chemokine , signal transduction , cancer research , apoptosis , immunology , akt1 , medicine , lung , chemistry , biology , microbiology and biotechnology , biochemistry
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 ( PI 3K) and its downstream signalling pathway in LMMHA ‐induced lung inflammatory responses. Our results indicate that pharmacological inhibition of PI 3K 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 PI 3K/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 PI 3K/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.