Second generation <scp>BTK</scp> inhibitors impair the anti‐fungal response of macrophages and neutrophils

Colado, Ana; Franco, José Luis Marín; Elías, Esteban Enrique; Amondarain, Mikele; Rubio, Maricef Vergara; Martínez, Valeria Sarapura; Cordini, Gregorio; Fuentes, Federico; Balboa, Luciana; Grecco, Horacio Fernández; Pavlovsky, Miguel Arturo; Bezares, Fernando; Morande, Pablo Elías; Giordano, Mirta; Gamberale, Romina; Borge, Mercedes

doi:10.1002/ajh.25816

Cited by 19 publications

(13 citation statements)

References 8 publications

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“…Studies with neutrophils from XLA patients demonstrated either that Btk deficiency did not impact on TLR-induced neutrophil activation and oxidative burst ( 68 ), or enhanced the production of reactive oxygen species ( 69 ). In contrast, recent studies with Btk inhibitors showed that Btk inhibition affected neutrophil function and decreased phagocytosis of fungi, fungi- and FcR-induced oxidative burst, and bacterial killing ( 70 , 71 ).…”

Section: Discussionmentioning

confidence: 84%

Bruton’s Tyrosine Kinase-Mediated Signaling in Myeloid Cells Is Required for Protective Innate Immunity During Pneumococcal Pneumonia

Porto¹,

Liu

Beer

et al. 2021

Front. Immunol.

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Bruton’s tyrosine kinase (Btk) is a cytoplasmic kinase expressed in B cells and myeloid cells. It is essential for B cell development and natural antibody-mediated host defense against bacteria in humans and mice, but little is known about the role of Btk in innate host defense in vivo. Previous studies have indicated that lack of (natural) antibodies is paramount for impaired host defense against Streptococcus (S.) pneumoniae in patients and mice with a deficiency in functional Btk. In the present study, we re-examined the role of Btk in B cells and myeloid cells during pneumococcal pneumonia and sepsis in mice. The antibacterial defense of Btk-/- mice was severely impaired during pneumococcal pneumosepsis and restoration of natural antibody production in Btk-/- mice by transgenic expression of Btk specifically in B cells did not suffice to protect against infection. Btk-/- mice with reinforced Btk expression in MhcII+ cells, including B cells, dendritic cells and macrophages, showed improved antibacterial defense as compared to Btk-/- mice. Bacterial outgrowth in Lysmcre-Btkfl/Y mice was unaltered despite a reduced capacity of Btk-deficient alveolar macrophages to respond to pneumococci. Mrp8cre-Btkfl/Y mice with a neutrophil specific paucity in Btk expression, however, demonstrated impaired antibacterial defense. Neutrophils of Mrp8cre-Btkfl/Y mice displayed reduced release of granule content after pulmonary installation of lipoteichoic acid, a gram-positive bacterial cell wall component relevant for pneumococci. Moreover, Btk deficient neutrophils showed impaired degranulation and phagocytosis upon incubation with pneumococci ex vivo. Taken together, the results of our study indicate that besides regulating B cell-mediated immunity, Btk is critical for regulation of myeloid cell-mediated, and particularly neutrophil-mediated, innate host defense against S. pneumoniae in vivo.

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Section: Discussionmentioning

confidence: 84%

Bruton’s Tyrosine Kinase-Mediated Signaling in Myeloid Cells Is Required for Protective Innate Immunity During Pneumococcal Pneumonia

Porto¹,

Liu

Beer

et al. 2021

Front. Immunol.

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“…Inhibitors of Src Family Kinases (SFKs), which act upstream of Syk, and of Bruton’s Tyrosine Kinase (Btk), which mediates phospholipase C activation downstream of Syk, also inhibited TDB-, Furfurman- and curdlan-induced ROS production ( Figures 6 A–6D) consistent with prior data in human neutrophils using PP2 (iSFK) and β-glucan beads ( Nani et al., 2015 ). While Btk has been shown to contribute to neutrophil ROS, phagocytosis, and overall mouse survival during C. albicans infection ( Colado et al., 2020 ; Strijbis et al., 2013 ), the role of SFKs and Btk in C. glabrata infection is unclear. Here, inhibitors of Syk, SFKs, and Btk also significantly reduced C. glabrata- and C. albicans -induced ROS production by DIV neutrophils ( Figures 6 E and 6F), suggesting that in addition to Syk ( Negoro et al., 2020 ) and SKAP2 ( Figure 5 ), C. glabrata -stimulated ROS also requires SFKs and Btk.…”

Section: Resultsmentioning

confidence: 99%

Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin and Candida stimulation

Nguyen

Adams

et al. 2021

iScience

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Summary Signaling cascades converting the recognition of pathogens to efficient inflammatory responses by neutrophils are critical for host survival. SKAP2, an adaptor protein, is required for reactive oxygen species (ROS) generation following neutrophil stimulation by integrins, formyl peptide receptors, and for host defense against the Gram-negative bacterial pathogens, Klebsiella pneumoniae and Yersinia pseudotuberculosis . Using neutrophils from murine HoxB8-immortalized progenitors, we show that SKAP2 in neutrophils is crucial for maximal ROS response to purified C-type lectin receptor agonists and to the fungal pathogens, Candida glabrata and Candida albicans , and for robust killing of C. glabrata . Inside-out signaling to integrin and Syk phosphorylation occurred independently of SKAP2 after Candida infection. However, Pyk2, ERK1/2, and p38 phosphorylation were significantly reduced after infection with C. glabrata and K. pneumoniae in Skap2−/− neutrophils. These data demonstrate the importance of SKAP2 in ROS generation and host defense beyond antibacterial immunity to include CLRs and Candida species .

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“…A recent report (Fiorcari et al, 2020), shows that ibrutinibor acalabrutinib-mediated BTK inhibition negatively affects CLLassociated macrophages during A. fumigatus infection. It was also reported that ibrutinib and acalabrutinib impaired M1 polarization in macrophages, a phenotype associated with an efficient anti−microbial immune response (Colado et al, 2020). Furthermore, treatment with ibrutinib was shown to reduce the phagocytic ability and increase the immunosuppressive profile of nurse-like cells exacerbating the expression of M2 markers (Fiorcari et al, 2016).…”

Section: Mechanisms Underlying Increased Incidence Of Infectionsmentioning

confidence: 94%

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Estupiñán

Berglöf

Zain

et al. 2021

Front. Cell Dev. Biol.

168

171

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The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.

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Second generation BTK inhibitors impair the anti‐fungal response of macrophages and neutrophils

Cited by 19 publications

References 8 publications

Bruton’s Tyrosine Kinase-Mediated Signaling in Myeloid Cells Is Required for Protective Innate Immunity During Pneumococcal Pneumonia

Bruton’s Tyrosine Kinase-Mediated Signaling in Myeloid Cells Is Required for Protective Innate Immunity During Pneumococcal Pneumonia

Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin and Candida stimulation

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

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