X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

O'Riordan, Caroline E; Purvis, Gareth S. D.; Collotta, Debora; Krieg, Nadine; Wissuwa, Bianka; Sheikh, Madeeha H; Alves, Gustavo Ferreira; Mohammad, Shireen; Callender, Lauren A.; Coldewey, Sina M.; Collino, Massimo; Greaves, David R.; Thiemermann, Christoph

doi:10.3389/fimmu.2020.581758

Cited by 26 publications

(32 citation statements)

References 73 publications

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“…In accordance with our data De Porto et al report that ibrutinib treatment reduces PMN recruitment in acute pulmonary inflammation evoked by antibiotic-treated pneumococcal pneumonia and suggest that ibrutinib has the potential to inhibit ongoing lung inflammation in an acute infectious setting (de Porto et al, 2019). O'Riordan and colleagues reported reduced infiltration of neutrophils in a model of polymicrobial sepsis in XID mice (O'Riordan et al, 2020). Decreased myeloid cells recruitment has also been reported in other inflammatory models, RA, obesity and cerebral ischaemia, when BTK had been systemically inhibited with BTK inhibitors (Weber et al, 2017b).…”

Section: Discussionsupporting

confidence: 92%

“…During the COVID-19 pandemic BTK has been shown to be activated in monocytes and intervention with the BTK inhibitor Acalabrutinib has been reported to reduce systemic inflammation in patients with severe COVID-19 (Roschewski et al, 2020). We and others have reported inhibition of BTK reduces NF-kB and the NLRP3 inflammasome activity in both murine and human macrophages, and reduces pro-inflammatory cytokine and chemokine production (O'Riordan et al, 2020)(Mao et al, 2020.…”

Section: Introductionmentioning

confidence: 97%

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Bruton’s tyrosine kinase (BTK) regulates myeloid cell recruitment during acute inflammation

Purvis

Aranda

Channon

et al. 2021

Preprint

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Bruton’s tyrosine kinase (BTK) is a non-receptor kinase best known for its role in B lymphocyte development that is critical for proliferation, and survival of leukaemia cells in B cell malignancies. However, BTK is expressed in myeloid cells, particularly monocytes and macrophages where its inhibition has been reported to exhibit anti-inflammatory properties. Therefore, we explored the role of BTK on the migration of myeloid cells in vitro and in vivo. Using the zymosan induced peritonitis model of sterile inflammation we demonstrated that acute (1 h prior to zymosan) inhibition of BTK using a wide range of FDA (Ibrutinib and Acalabrutinib) and non-FDA approved inhibitors (ONO-4059, CNX-774, Olumatinib and LFM-A13) reduced neutrophil and monocyte recruitment. XID mice, which have a point mutation in the Btk gene had reduced neutrophil and monocyte recruitment to the peritoneum following zymosan challenge. To better understand the role of BTK in myeloid cell recruitment we investigated both chemotaxis and chemokine production in monocytes and macrophages. Pharmacological or genetic inhibition of BTK signalling substantially reduced human monocyte and murine macrophage chemotaxis to a range of chemoattractants (complement C5a and CCL2). We also demonstrated that inhibition of BTK in tissue resident macrophages significantly decreases chemokine secretion by reducing NF-kB activity and Akt signalling. Our work has identified a new role of BTK in regulating myeloid cell recruitment via two mechanisms, 1) reducing monocyte/macrophages’ ability to undergo chemotaxis, and 2) reducing chemokine secretion, via reduced NF-kB activity in tissue resident macrophages.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 97%

Bruton’s tyrosine kinase (BTK) regulates myeloid cell recruitment during acute inflammation

Purvis

Aranda

Channon

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…More recently, cardiac failure in the wake of sepsis was studied in an experimental model under ibrutinib and acalabrutinib administration (O'Riordan et al, 2019 ). Btk -deficient Xid mice were also protected in a polymicrobial sepsis model, with reduced NLRP3 activation contributing to the phenotype (O'Riordan et al, 2020 ). Interestingly, BTK inhibition reduced NLRP3 protein levels and IL-1 in the serum.…”

Section: Evidence From Preclinical In Vivo Models mentioning

confidence: 99%

Targeting the NLRP3 Inflammasome via BTK

Weber

2021

Front. Cell Dev. Biol.

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The NLRP3 inflammasome represents a critical inflammatory machinery driving pathology in many acute (e. g., myocardial infarction or stroke) and chronic (Alzheimer's disease, atherosclerosis) human disorders linked to the activity of IL-1 cytokines. Although the therapeutic potential of NLRP3 is undisputed, currently no clinically approved therapies exist to target the NLRP3 inflammasome directly. The recent discovery of BTK as a direct and positive regulator of the NLRP3 inflammasome has, however, raised the intriguing possibility of targeting the NLRP3 inflammasome via existing or future BTK inhibitors. Here, I review the mechanistic basis for this notion and discuss the molecular and cellular role of BTK in the inflammasome process. Specific attention will be given to cell-type dependent characteristics and differences that may be relevant for targeting approaches. Furthermore, I review recent (pre-)clinical evidence for effects of BTK inhibitors on NLRP3 activity and highlight and discuss open questions and future research directions. Collectively, the concept of targeting BTK to target NLRP3-dependent inflammation will be explored comprehensively at the molecular, cellular and therapeutic levels.

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“…It has been observed that the regulatory effects of BTK inhibition on the NLRP3 inflammasome vary in different mouse models. BTK deficiency has been shown to promote NLRP3 inflammasome activation and induce IL-1β-mediated colitis, but it also alleviates other diseases, such as ischemic brain injury, diet-induced metabolic inflammation and polymicrobial sepsis ( 26 - 28 ). On this basis, the association between BTK and the NLRP3 inflammasome in DN was examined in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, BTK has attracted increased attention as a regulator of NLRP3. It has been demonstrated that the inhibition of BTK can reduce the inflammatory response by decreasing the activation of the NLRP3 inflammasome in numerous diseases, such as ischemic brain injury, diet-induced metabolic inflammation and polymicrobial sepsis ( 26 - 28 ). However, the role of BTK in DN remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Bruton's tyrosine kinase regulates macrophage‑induced inflammation in the diabetic kidney via NLRP3 inflammasome activation

Zhao

Chen

et al. 2021

Int J Mol Med

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It has been previously reported that macrophages may be involved in diabetic nephropathy (DN) development. Furthermore, Bruton's tyrosine kinase (BTK) may participate in macrophage activation and lead to the release of inflammatory mediators. The main aim of the present study was to analyze the association between renal BTK expression and clinical indicators. Moreover, BTK knockout mice were used to establish a diabetic model for further research. The results demonstrated that BTK was activated in the kidneys of patients with DN and was associated with the progression of proteinuria, creatinine levels, estimated glomerular filtration rate and pathological changes in the kidneys of patients with DN. Furthermore, BTK knockout was observed to reduce urinary protein excretion, alleviate renal injury and decrease renal inflammation in diabetic mice. This protection may be attributed to BTK-induced suppression of the activation of the Nod-like receptor (NLR) family pyrin domain containing 3 inflammasome. Collectively, it has been demonstrated in the present study that BTK may be a potential target for DN treatment.

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X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

Cited by 26 publications

References 73 publications

Bruton’s tyrosine kinase (BTK) regulates myeloid cell recruitment during acute inflammation

Bruton’s tyrosine kinase (BTK) regulates myeloid cell recruitment during acute inflammation

Targeting the NLRP3 Inflammasome via BTK

Bruton's tyrosine kinase regulates macrophage‑induced inflammation in the diabetic kidney via NLRP3 inflammasome activation

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