Abrocitinib Attenuates Microglia-Mediated Neuroinflammation after Traumatic Brain Injury via Inhibiting the JAK1/STAT1/NF-κB Pathway

Abstract

Background and Purpose: Neuroinflammation has been shown to play a critical role in secondary craniocerebral injury, leading to poor outcomes for TBI patients. Abrocitinib, a Janus kinase1 (JAK1) selective inhibitor approved to treat atopic dermatitis (AD) by the Food and Drug Administration (FDA), possesses a novel anti-inflammatory effect. In this study, we investigated whether abrocitinib could ameliorate neuroinflammation and exert a neuroprotective effect in traumatic brain injury (TBI) models. Methods: First, next-generation sequencing (NGS) was used to select genes closely related to neuroinflammation after TBI. Then, magnetic resonance imaging (MRI) was used to dynamically observe the changes in traumatic focus on the 1st, 3rd, and 7th days after the induction of fluid percussion injury (FPI). Moreover, abrocitinib’s effects on neurobehaviors were evaluated. A routine peripheral blood test was carried out and Evans blue dye extravasation, cerebral cortical blood flow, the levels of inflammatory cytokines, and changes in the numbers of inflammatory cells were evaluated to investigate the function of abrocitinib on the 1st day post-injury. Furthermore, the JAK1/signal transducer and activator of transcription1 (STAT1)/nuclear factor kappa (NF-κB) pathway was assessed. Results: In vivo, abrocitinib treatment was found to shrink the trauma lesions. Compared to the TBI group, the abrocitinib treatment group showed better neurological function, less blood-brain barrier (BBB) leakage, improved intracranial blood flow, relieved inflammatory cell infiltration, and reduced levels of inflammatory cytokines. In vitro, abrocitinib treatment was shown to reduce the pro-inflammatory M1 microglia phenotype and shift microglial polarization toward the anti-inflammatory M2 phenotype. The WB and IHC results showed that abrocitinib played a neuroprotective role by restraining JAK1/STAT1/NF-κB levels after TBI. Conclusions: Collectively, abrocitinib treatment after TBI is accompanied by improvements in neurological function consistent with radiological, histopathological, and biochemical changes. Therefore, abrocitinib can indeed reduce excessive neuroinflammation by restraining the JAK1/STAT1/NF-κB pathway.

Spleen tyrosine kinase inhibitor R406 has both antiviral and anti‐inflammatory effects on severe influenza A infection

“…22 However, many studies have demonstrated that activation of STAT-1 associated pathways (e.g., JAK2/STAT1, JAK-STAT1/ STAT3, and STAT1/NF-κB) facilitates acute tissue injury, including lung and kidney. [23][24][25] In this study, R406 treatment remarkably decreased the intracellular signaling molecular levels of multiple pathways including STAT-3 and NF-κB in A549 in the cell inflammation model with CA04 infection. Furthermore, our study demonstrated that SYK inhibitor treatment decreased the pathogenicity and mortality of lethal influenza virus in mice.…”

“…Previous studies have demonstrated that SYK phosphorylation can activate STAT1/3, which plays a crucial role in innate immunity by directing the transcriptional response to IFNs and other cytokines, thereby protecting the host from pathogen infection at the early stage of viral infection, 18,19 and exert its secondary messenger functions, triggering ROS production, 20 accelerated phagocytosis 21 as well as the production of pro‐inflammatory cytokines 22 . However, many studies have demonstrated that activation of STAT‐1 associated pathways (e.g., JAK2/STAT1, JAK‐STAT1/STAT3, and STAT1/NF‐κB) facilitates acute tissue injury, including lung and kidney 23–25 . In this study, R406 treatment remarkably decreased the intracellular signaling molecular levels of multiple pathways including STAT‐3 and NF‐κB in A549 in the cell inflammation model with CA04 infection.…”

ePhyscion prevents induction of optic nerve injury in rats via inhibition of the JAK2/STAT3 pathway

“…Relevant studies reported that neuropathy such as neuron damage could lead to increased secretion of IL-6 and IL-21, as well as activation of the JAK-STAT pathway and phosphorylation of STAT3, which could induce immune response. Neuron damage could also activate glial cells, including microglia and astrocytes, and induce ATP, pro-inflammatory factors, induced ROS, NOS, prostaglandin, excitatory amino acids and release of other substances, causing persistent inflammation (33,34). The present study indicated that the phosphorylation levels of JAK2 and STAT3 were upregulated in HAPI cells following their treatment with IFN-β.…”

circRNA-PTPN4 mediated regulation of FOXO3 and ZO-1 expression: implications for blood–brain barrier integrity and cognitive function in uremic encephalopathy

“…Brain homogenates were centrifuged at 14,000 rpm for 30 min, and the supernatant containing Evans Blue was transferred to a 96-well plate, with 200 µL per well, including replicates. Optical density at 620 nm was measured using a pre-warmed microplate reader (Li et al 2022 ).…”