BTK inhibitor ibrutinib reduces LPS-induced inflammation in C8-B4 microglia

TL;DR

This study shows that the drug ibrutinib can reduce inflammation in microglial cells, which may help treat neurodegenerative diseases.

Contribution

The study reveals that ibrutinib mitigates LPS-induced inflammation in microglia via the TLR4/NF-κβ and Nrf2/HO-1 pathways.

Findings

Ibrutinib reduces LPS-induced nitric oxide and NOS3 expression in microglia.

Ibrutinib decreases TNF-α and modulates TLR4/NF-κβ pathways in LPS-activated microglia.

Ibrutinib lowers ROS production and supports mitochondrial function in microglial cells.

Abstract

In this study, we examined the potential of Bruton tyrosine kinase (BTK) inhibitor ibrutinib to mitigate neuroinflammation in C8-B4 microglial cells activated by the bacterial endotoxin lipopolysaccharide (LPS). Our objective was to enhance understanding of its mechanism of action, particularly in relation to its anti-inflammatory, and antioxidant potential of ibrutinib. Here, mouse microglial C8-B4 cells were treated with ibrutinib (1 and 10 μM) or vehicle (1 % DMSO) for 1 h, followed by lipopolysaccharide (LPS 1 μg/mL) for 23 h. We observed that ibrutinib significantly decreased LPS-induced nitric oxide levels and nitric oxide synthase 3 (NOS3) expression. In parallel, ibrutinib decreased cell senescence induced by LPS in microglia. Ibrutinib notably diminished the elevation of tumor necrosis factor-α (TNF-α), triggered by LPS in C8-B4 microglia. It also modulated Toll-like receptor 4 (TLR4) expression induced by LPS. Moreover, ibrutinib markedly lowered the augmented levels of nuclear factor kappa beta (NF-κβ) and phosphorylated NF-kβ (pNF-κβ) induced by LPS, indicating its capacity to mitigate LPS-induced neuroinflammatory reactions by hindering TLR4/NF-κβ pathway. Additionally, these beneficial effects are associated with regulation of the Nrf2/HO-1 pathway. The present results suggest that treatment with ibrutinib may contribute to the preservation of mitochondrial function, as evidenced by its ability to reduce reactive oxygen species (ROS) production. While these findings provide important insights into the potential neuroprotective mechanisms of ibrutinib, the precise molecular pathways involved in mitochondrial preservation require further investigation. Collectively, these data support the therapeutic potential of ibrutinib in mitigating neuroinflammation-related mitochondrial dysfunction and highlight its promise as a candidate for treating neurodegenerative disorders characterized by oxidative stress and impaired mitochondrial integrity.

See also the graphical abstract(Fig. 1).

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