Effect on neutrophil migration and antimicrobial functions by the Bruton's tyrosine kinase inhibitors tolebrutinib, evobrutinib and fenebrutinib

Mirre De Bondt; Janne Renders; Paloma Petit de Prado; Nele Berghmans; Noëmie Pörtner; Lotte Vanbrabant; Vívian Louise Soares de Oliveira; Gayel Duran; Paulien Baeten; Bieke Broux; Mieke Gouwy; Patrick Matthys; Niels Hellings; Sofie Struyf

doi:10.1093/jleuko/qiae160

Effect on neutrophil migration and antimicrobial functions by the Bruton's tyrosine kinase inhibitors tolebrutinib, evobrutinib and fenebrutinib

J Leukoc Biol. 2024 Jul 8:qiae160. doi: 10.1093/jleuko/qiae160. Online ahead of print.

Authors

Mirre De Bondt^{1

2

3}, Janne Renders¹, Paloma Petit de Prado¹, Nele Berghmans¹, Noëmie Pörtner¹, Lotte Vanbrabant¹, Vívian Louise Soares de Oliveira¹, Gayel Duran^{2

3}, Paulien Baeten^{2

3}, Bieke Broux^{2

3}, Mieke Gouwy¹, Patrick Matthys⁴, Niels Hellings^{2

3}, Sofie Struyf¹

Affiliations

¹ Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Belgium.
² Neuro Immune Connections & Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Belgium.
³ University MS Center, Pelt-Hasselt, Campus Hasselt, Belgium.
⁴ Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Belgium.

PMID: 38976501
DOI: 10.1093/jleuko/qiae160

Abstract

Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease that is still incurable. Nowadays, a variety of new drugs are being developed to prevent excessive inflammation and halt neurodegeneration. Among these are the inhibitors of Bruton's tyrosine kinase (BTK). Being indispensable for B cells, this enzyme became an appealing therapeutic target for autoimmune diseases. Recognizing the emerging importance of BTK in myeloid cells, we investigated the impact of upcoming BTK inhibitors on neutrophil functions. Although adaptive immunity in MS has been thoroughly studied, unanswered questions about the pathogenesis can be addressed by studying the effects of candidate MS drugs on innate immune cells such as neutrophils, previously overlooked in MS. In this study, we used three BTK inhibitors (evobrutinib, fenebrutinib and tolebrutinib), and found that they reduce neutrophil activation by the bacterial peptide N-formylmethionyl-leucyl-phenylalanine and the chemokine interleukin 8/CXCL8. Furthermore, they diminished the production of reactive oxygen species and release of neutrophil extracellular traps. Additionally, the production of CXCL8 and interleukin-1β in response to inflammatory stimuli was decreased. Inhibitory effects of the drugs on neutrophil activation were not related to toxicity. Instead, BTK inhibitors prolonged neutrophil survival in an inflammatory environment. Finally, treatment with BTK inhibitors decreased neutrophil migration towards CXCL8 in a Boyden chamber assay but not in a trans endothelial set-up. Also, in vivo CXCL1-induced migration was unaffected by BTK inhibitors. Collectively, this study provides novel insights into the impact of BTK inhibitors on neutrophil functions, thereby holding important implications for autoimmune or hematological diseases where BTK is crucial.

Keywords: Autoimmunity; Bruton’s tyrosine kinase signaling; innate immunity; pharmacological inhibitors; sphingosine-1-phosphate receptors.