Journal
INTERNATIONAL IMMUNOPHARMACOLOGY
Volume 113, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.intimp.2022.109469
Keywords
Innate immunity; Bruton?s tyrosine kinase; Neutrophils; Macrophages; Acute peritonitis
Categories
Funding
- National Natural Science Foundation of China [8217033129]
- Medical Science and Technology Project of Henan Province [LHGJ20220416]
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This study found that Ibrutinib can significantly inhibit the activation of neutrophils and macrophages by inhibiting the BTK-PLC gamma 2-PKC signaling pathway, thus playing a therapeutic role in acute inflammatory diseases.
Timely treatment of acute inflammatory reactions induced by fungi or bacteria is essential to prevent infectious damage. Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor which is used to treat various lymphoid cancers. It is also known that BTK plays important roles in innate immunity and inflammatory response. In the present study, we investigated the regulatory effects of Ibrutinib on the activation of neutrophils and macrophages and its therapeutic effects on acute peritonitis. In addition, we also studied its anti-inflammatory mechanisms. The results showed that Ibrutinib inhibited the expression and secretion of inflammatory factors in macrophages induced by multiple Toll-like receptor (TLR) agonists. In the study of neutrophils, Ibrutinib selectively suppressed the activation, superoxide release, and calcium influx of neutrophils stimulated by zymosan. Furthermore, in zymosan-induced mice acute peritonitis, Ibrutinib significantly reduced the infiltration of neutrophils into peritoneal cavity, the release of myeloperoxidase (MPO) and beta-glucuronidase as well as the production of in-flammatory factors in peritoneal cavity. In mechanism study, Ibrutinib selectively inhibited the phosphorylation of PLC gamma 2, PKC delta, and ERK1/2 in neutrophils induced by zymosan. Collectively, Ibrutinib can significantly inhibit the activation of neutrophils and macrophages by inhibiting BTK-PLC gamma 2-PKC signaling pathway, and has great potential to be developed into therapeutic drug for acute inflammatory diseases.
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