Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice

Abstract

BackgroundThe FDA-approved small-molecule drug ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib inhibits Bruton’s tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. However, the potential regulation of neuroinflammatory responses in the brain by ibrutinib has not been comprehensively examined.MethodsBV2 microglial cells were treated with ibrutinib (1 μM) or vehicle (1% DMSO), followed by lipopolysaccharide (LPS; 1 μg/ml) or PBS. RT-PCR, immunocytochemistry, and subcellular fractionation were performed to examine the effects of ibrutinib on neuroinflammatory responses. In addition, wild-type mice were sequentially injected with ibrutinib (10 mg/kg, i.p.) or vehicle (10% DMSO, i.p.), followed by LPS (10 mg/kg, i.p.) or PBS, and microglial and astrocyte activations were assessed using immunohistochemistry.ResultsIbrutinib significantly reduced LPS-induced increases in proinflammatory cytokine levels in BV2 microglial and primary microglial cells but not in primary astrocytes. Ibrutinib regulated TLR4 signaling to alter LPS-induced proinflammatory cytokine levels. In addition, ibrutinib significantly decreased LPS-induced increases in p-AKT and p-STAT3 levels, suggesting that ibrutinib attenuates LPS-induced neuroinflammatory responses by inhibiting AKT/STAT3 signaling pathways. Interestingly, ibrutinib also reduced LPS-induced BV2 microglial cell migration by inhibiting AKT signaling. Moreover, ibrutinib-injected wild-type mice exhibited significantly reduced microglial/astrocyte activation and COX-2 and IL-1β proinflammatory cytokine levels.ConclusionsOur data provide insights on the mechanisms of a potential therapeutic strategy for neuroinflammation-related diseases.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1308-0) contains supplementary material, which is available to authorized users.

Oral Administration of Alpha Linoleic Acid Rescues Aβ-Induced Glia-Mediated Neuroinflammation and Cognitive Dysfunction in C57BL/6N Mice

“…Our previous studies also suggested that TLR4 inhibition in Aβ-treated mice (using a plant-derived flavonoid) protects mouse brains against neuroinflammation [17]. Similarly, other studies suggested that the inhibition of TLR4 is protective in LPS-injected mice and BV-2 microglial cells [49]. Here, we found a marked decrease in the levels of TLR4, GFAP, and Iba-1 in the Aβ 1-42 + ALA-cotreated group.…”

Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway

“…It has been proved that the active migration of microglial cells is closely associated with the inflammatory responses [24,25]. Therefore, we then assessed whether HSR1101 could arrest LPS-stimulated migration of BV2 cells.…”

Ibrutinib alleviated LPS-induced neuroinflammation and synaptic defects in a mouse model of depression

“…LPS is widely used to induce neuroin ammation [2,3,49,54,62]. Numerous studies showed that LPS treatment could induce central in ammatory response associated with proin ammatory cytokines production, glial cell activation, as well as ROS and RNS generation [2,5,7,40,44,47,54,[63][64][65][66][67][68][69].…”

“…It has been shown that LPS administration accelerates ROS/RNS production in the brain tissues [32,46,47]. Moreover, antioxidants modulate the pathophysiology of chronic in ammation, indicating a bene cial role in neuroin ammation [48][49][50][51]. Herein, the ROS ( Fig.…”

“…Moreover, it can cross the blood-brain barrier as shown in several preclinical studies [28,29]. As an immunomodulator, ibrutinib affects the function of the peripheral innate and acquired immune cells including macrophages, B cells, T cells, and natural killer cells [30,31]. However, its role against center neuroin ammation and depression has not to be investigated comprehensively so far.…”