Ibrutinib Abrogates TREM-1 Mediated Neutrophil Activation

Triggering receptor expressed on myeloid cells 1 (TREM-1) is an activating receptor on neutrophils (PMN) and important in the innate host defence against microbial pathogens. Here we examined the influence of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib on TREM-1 dependent activation of human PMNs. Firstly, ibrutinib specifically inhibited TREM-1 mediated PMN activation of the oxidative burst and CD62L shedding, whereas TLR mediated activation remained unaffected. Correspondingly, ibrutinib suppressed ERK phosphorylation after TREM-1, but not after TLR ligation. To clarify whether this TREM-1 specific effect of ibrutinib was also relevant in vivo , we treated mice with ibrutinib, and analyzed fungal clearance in vivo upon pulmonary challenge with A. fumigatus and PMN activation ex vivo upon TREM-1 or TLR ligation, again finding that TREM-1, but not TLR induced activation was suppressed. Equivalent results were obtained in PMNs of six lymphoma patients under treatment with ibrutinib. In summary, BTK plays an important role in TREM-1 mediated PMN activation, providing a potential mechanism for the frequently observed infectious complications in patients treated with ibrutinib, and fosters studies using this drug as a novel tool to modulate TREM-1 activity for therapeutic purposes, i. e. in sepsis or autoimmune diseases. Disclosures Hess: Pfizer: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Roche: Honoraria; Novartis: Honoraria.