Bruton's tyrosine kinase (BTK) and matrix metalloproteinase-9 (MMP-9) regulate NLRP3 inflammasome-dependent cytokine and neutrophil extracellular trap responses in primary neutrophils

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Leal, Vinicius N. C. ; Bork, Francesca ; Tortola, Maria Mateo ; von Guilleaume, Juli-Christin ; Greve, Carsten L. ; Bugl, Stefanie ; Danker, Bettina ; Bittner, Zsofia A. ; Grimbacher, Bodo ; Pontillo, Alessandra ; Weber, Alexander N. R.

• Tipo de documento: Artigo Científico
• Fonte: Journal of Allergy and Clinical Immunology; v. 155, n. 2, p. 14-pg., 2025-02-05.

Resumo

Background: Inflammation is a double-edged state of immune activation that is required to resolve threats harmful to the host, but can also cause severe collateral damage. Polymorphonuclear neutrophils (PMNs), the primary leukocyte population in humans, mediate inflammation through the release of cytokines and neutrophil extracellular traps (NETs). Although the pathophysiological importance of NETs is unequivocal, the multiple molecular pathways driving NET release are not fully defined. Recently, NET release was linked to the NLRP3 inflammasome, which is regulated by Bruton's tyrosine kinase (BTK) in macrophages. Objective: As NLRP3 inflammasome regulation by BTK has not been studied in neutrophils, we explored a potential regulatory role of BTK in primary murine and human neutrophils and matched monocytes or macrophages from Btk-deficient versus wild-type mice, or from healthy donors versus BTK-deficient patients with X-linked agammaglobulinemia. Methods: Cytokine, myeloperoxidase, and matrix metalloproteinase-9 (MMP-9) release were quantified by ELISA, NET release, and inflammasome formation by immunofluorescence microscopy. Results: Surprisingly, in both mouse and human primary neutrophils, we observed a significant increase in NLRP3 inflammasome-dependent IL-1(3 and NETs when BTK was absent or inhibited, whereas IL-1(3 release was decreased in corresponding primary mouse macrophages or human PBMCs. This suggests a novel negative regulatory role of BTK in terms of neutrophil NLRP3 activation. IL-1(3 and NET release in both mouse and human primary neutrophils was strictly dependent on NLRP3, caspase-1 and, surprisingly, MMP-9. Conclusions: This study highlights BTK and MMP-9 as novel and versatile inflammasome regulators and may have implications for the clinical use of BTK inhibitors. (J Allergy Clin Immunol 2025;155:569-82.) (AU)

• Processo FAPESP: 20/15323-3 - Desregulação do inflamassoma na ativação de neutrófilos e endotélio em resposta a SARS-CoV-2 e contribuição para desenvolvimento de COVID-19 grave
• Beneficiário: Vinícius Nunes Cordeiro Leal
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 21/13049-4 - Mecanismos moleculares envolvidos na regulação do NLRP3 inflamassoma em neutrófilos
• Beneficiário: Vinícius Nunes Cordeiro Leal
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado