Bruton’s Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia

Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton’s tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells...

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Autores principales:	Leigh Naylor-Adamson, Anisha R. Chacko, Zoe Booth, Stefano Caserta, Jenna Jarvis, Sujoy Khan, Simon P. Hart, Francisco Rivero, David J. Allsup, Mònica Arman
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	platelet FcγRIIA Staphylococcus aureus Escherichia coli Bruton’s tyrosine kinase inhibitor ibrutinib Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/ae5be3bf207c4bf3ac689a97a416281c
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spelling	oai:doaj.org-article:ae5be3bf207c4bf3ac689a97a416281c2021-12-01T13:36:31ZBruton’s Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia1664-322410.3389/fimmu.2021.766272https://doaj.org/article/ae5be3bf207c4bf3ac689a97a416281c2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.766272/fullhttps://doaj.org/toc/1664-3224Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton’s tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells and can be targeted by ibrutinib. In platelets, ibrutinib therapy is associated with bleeding complications mostly due to off-target effects. But the ability of platelets to respond to bacteria in CLL, and the potential impact of ibrutinib on platelet innate immune functions remain unknown. FcγRIIA is a tyrosine kinase-dependent receptor critical for platelet activation in response to IgG-coated pathogens. Crosslinking of this receptor with monoclonal antibodies causes downstream activation of Btk and Tec in platelets, however, this has not been investigated in response to bacteria. We asked whether ibrutinib impacts on FcγRIIA-mediated activation of platelets derived from CLL patients and healthy donors after exposure to Staphylococcus aureus Newman and Escherichia coli RS218. Platelet aggregation, α-granule secretion and integrin αIIbβ3-dependent scavenging of bacteria were detected in CLL platelets but impaired in platelets from ibrutinib-treated patients and in healthy donor-derived platelets exposed to ibrutinib in vitro. While levels of surface FcγRIIA remained unaffected, CLL platelets had reduced expression of integrin αIIbβ3 and GPVI compared to controls regardless of therapy. In respect of intracellular signaling, bacteria induced Btk and Tec phosphorylation in both CLL and control platelets that was inhibited by ibrutinib. To address if Btk is essential for platelet activation in response to bacteria, platelets derived from X-linked agammaglobulinemia patients (lacking functional Btk) were exposed to S. aureus Newman and E. coli RS218, and FcγRIIA-dependent aggregation was observed. Our data suggest that ibrutinib impairment of FcγRIIA-mediated platelet activation by bacteria results from a combination of Btk and Tec inhibition, although off-target effects on additional kinases cannot be discarded. This is potentially relevant to control infection-risk in CLL patients and, thus, future studies should carefully evaluate the effects of CLL therapies, including Btk inhibitors with higher specificity for Btk, on platelet-mediated immune functions. Leigh Naylor-AdamsonAnisha R. ChackoZoe BoothStefano CasertaJenna JarvisSujoy KhanSimon P. HartFrancisco RiveroDavid J. AllsupDavid J. AllsupMònica ArmanFrontiers Media S.A.articleplateletFcγRIIAStaphylococcus aureusEscherichia coliBruton’s tyrosine kinase inhibitoribrutinibImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	platelet FcγRIIA Staphylococcus aureus Escherichia coli Bruton’s tyrosine kinase inhibitor ibrutinib Immunologic diseases. Allergy RC581-607
spellingShingle	platelet FcγRIIA Staphylococcus aureus Escherichia coli Bruton’s tyrosine kinase inhibitor ibrutinib Immunologic diseases. Allergy RC581-607 Leigh Naylor-Adamson Anisha R. Chacko Zoe Booth Stefano Caserta Jenna Jarvis Sujoy Khan Simon P. Hart Francisco Rivero David J. Allsup David J. Allsup Mònica Arman Bruton’s Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia
description	Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton’s tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells and can be targeted by ibrutinib. In platelets, ibrutinib therapy is associated with bleeding complications mostly due to off-target effects. But the ability of platelets to respond to bacteria in CLL, and the potential impact of ibrutinib on platelet innate immune functions remain unknown. FcγRIIA is a tyrosine kinase-dependent receptor critical for platelet activation in response to IgG-coated pathogens. Crosslinking of this receptor with monoclonal antibodies causes downstream activation of Btk and Tec in platelets, however, this has not been investigated in response to bacteria. We asked whether ibrutinib impacts on FcγRIIA-mediated activation of platelets derived from CLL patients and healthy donors after exposure to Staphylococcus aureus Newman and Escherichia coli RS218. Platelet aggregation, α-granule secretion and integrin αIIbβ3-dependent scavenging of bacteria were detected in CLL platelets but impaired in platelets from ibrutinib-treated patients and in healthy donor-derived platelets exposed to ibrutinib in vitro. While levels of surface FcγRIIA remained unaffected, CLL platelets had reduced expression of integrin αIIbβ3 and GPVI compared to controls regardless of therapy. In respect of intracellular signaling, bacteria induced Btk and Tec phosphorylation in both CLL and control platelets that was inhibited by ibrutinib. To address if Btk is essential for platelet activation in response to bacteria, platelets derived from X-linked agammaglobulinemia patients (lacking functional Btk) were exposed to S. aureus Newman and E. coli RS218, and FcγRIIA-dependent aggregation was observed. Our data suggest that ibrutinib impairment of FcγRIIA-mediated platelet activation by bacteria results from a combination of Btk and Tec inhibition, although off-target effects on additional kinases cannot be discarded. This is potentially relevant to control infection-risk in CLL patients and, thus, future studies should carefully evaluate the effects of CLL therapies, including Btk inhibitors with higher specificity for Btk, on platelet-mediated immune functions.
format	article
author	Leigh Naylor-Adamson Anisha R. Chacko Zoe Booth Stefano Caserta Jenna Jarvis Sujoy Khan Simon P. Hart Francisco Rivero David J. Allsup David J. Allsup Mònica Arman
author_facet	Leigh Naylor-Adamson Anisha R. Chacko Zoe Booth Stefano Caserta Jenna Jarvis Sujoy Khan Simon P. Hart Francisco Rivero David J. Allsup David J. Allsup Mònica Arman
author_sort	Leigh Naylor-Adamson
title	Bruton’s Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia
title_short	Bruton’s Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia
title_full	Bruton’s Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia
title_fullStr	Bruton’s Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia
title_full_unstemmed	Bruton’s Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia
title_sort	bruton’s tyrosine kinase inhibitors impair fcγriia-driven platelet responses to bacteria in chronic lymphocytic leukemia
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/ae5be3bf207c4bf3ac689a97a416281c
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Bruton’s Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia

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