Syk Activation in Circulating and Tissue Innate Immune Cells in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Prendecki, Maria; Gulati, Kavita; Pisacano, Noelle; Pinheiro, Damilola; Bhatt, Tejal R.; Mawhin, Marie‐Anne; Toulza, Frédéric; Masuda, Esteban; Cowburn, Andrew S.; Lodge, Katharine M; Tam, Frederick W.K.; Roufosse, Candice; Pusey, Charles D.; McAdoo, Stephen P.

doi:10.1002/art.42321

Cited by 5 publications

(4 citation statements)

References 47 publications

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“…In contrast, Mulder et al demonstrated that FcγRII was critically implicated in ANCA-induced neutrophil activation [ 8 ]. Although there remains a controversy about the pathways, Prendecki et al recently demonstrated that a signal transducer Syk, which acts downstream of FcγRs, was activated in patients with AAV [ 24 ]. These findings suggested that ANCA-induced FcγR-mediated signals are critical for neutrophil activation in AAV pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Bruton’s tyrosine kinase is a possible therapeutic target in microscopic polyangiitis

Nakade,

Tamura,

Hashimoto

et al. 2023

Arthritis Res Ther

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Background Bruton’s tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA. Methods Various doses of tirabrutinib or vehicle were orally administered to Sprague–Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation. Results Tirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib. Conclusions The Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA.

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Section: Discussionmentioning

confidence: 99%

Bruton’s tyrosine kinase is a possible therapeutic target in microscopic polyangiitis

Nakade,

Tamura,

Hashimoto

et al. 2023

Arthritis Res Ther

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“…Mechanistically, ANCA immunoglobulin G could phosphorylate SYK at Y348. Accordingly, SYK inhibition could inhibit ANCA-mediated PLCγ/Vav/Ras/mitogen-activated protein kinases/NF-κB signaling [ 124 , 125 ]. Collectively, SYK is involved in the HF process by inducing myocardial fibrosis via activation of the TGF-β1/Smad3 pathway in cardiac tissues and modulating immune responses.…”

Section: Syk In Heart Failurementioning

confidence: 99%

Spleen tyrosine kinase (SYK) signals are implicated in cardio-cerebrovascular diseases

Li¹,

Wang²,

Zou³

et al. 2023

Heliyon

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“…Syk phosphorylation in neutrophils is increased in patients with active AAV, and is correlated with ANCA titers. Syk inhibition prevents the production of IL-8 and ROS by neutrophils in vitro ( 62 ). The treatment of fostamatinib, Syk inhibitor, is protective in AAV model rats induced by immunization with human MPO with the improvement of organ injury and and renal dysfunction ( 63 ).…”

Section: Targeting Nets Signaling Pathway In Aavmentioning

confidence: 99%

The involvement of NETs in ANCA-associated vasculitis

Shiratori-Aso,

Nakazawa

2023

Front. Immunol.

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Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a serious autoimmune disease that is characterized by vascular necrosis. The pathogenesis of AAV includes ANCA-mediated neutrophil activation, subsequent release of inflammatory cytokines and reactive oxygen species (ROS), and formation of neutrophil extracellular traps (NETs). Excessive NETs could participate not only in ANCA-mediated vascular injury but also in the production of ANCAs per se as autoantigens. Thus, a vicious cycle of NET formation and ANCA production is critical for AAV pathogenesis. Elucidating the molecular signaling pathways in aberrant neutrophil activation and NETs clearance systems will allow specific therapeutics to regulate these pathways. Currently, standard therapy with high doses of glucocorticoids and immunosuppressants has improved outcomes in patients with AAV. However, AAV frequently develops in elderly people, and adverse effects such as severe infections in the standard regimens might contribute to the mortality. Mechanistically, cytokines or complement factors activate and prime neutrophils for ANCA-binding; thus, C5a receptor blocker has garnered attention as potential replacement for glucocorticoids in clinical settings. Recent studies have demonstrated that receptor-interacting protein kinases (RIPK3) and cyclophilin D (CypD), which regulate cell necrosis, may be involved in ANCA-induced NETs formation. Meanwhile, targeting NETs clearance, including the addition of deoxyribonuclease I (DNase I) and macrophage engulfment, may improve vasculitis. In this review, we focus on the pathogenesis of NETs and discuss potential targeted therapies for AAV based on recent experimental evidence.

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Syk Activation in Circulating and Tissue Innate Immune Cells in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Cited by 5 publications

References 47 publications

Bruton’s tyrosine kinase is a possible therapeutic target in microscopic polyangiitis

Bruton’s tyrosine kinase is a possible therapeutic target in microscopic polyangiitis

Spleen tyrosine kinase (SYK) signals are implicated in cardio-cerebrovascular diseases

The involvement of NETs in ANCA-associated vasculitis

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