Folic acid deficiency exacerbates the inflammatory response of astrocytes after ischemia‐reperfusion by enhancing the interaction between IL‐6 and JAK‐1/pSTAT3

Abstract

Aim To demonstrate the role of IL‐6 and pSTAT3 in the inflammatory response to cerebral ischemia/reperfusion following folic acid deficiency (FD). Methods The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in adult male Sprague‐Dawley rats in vivo, and cultured primary astrocytes were exposed to oxygen‐glucose deprivation/reoxygenation (OGD/R) to emulate ischemia/reperfusion injury in vitro. Results Glial fibrillary acidic protein (GFAP) expression significantly increased in astrocytes of the brain cortex in the MCAO group compared to the SHAM group. Nevertheless, FD did not further promote GFAP expression in astrocytes of rat brain tissue after MCAO. This result was further confirmed in the OGD/R cellular model. In addition, FD did not promote the expressions of TNF‐α and IL‐1β but raised IL‐6 (Peak at 12 h after MCAO) and pSTAT3 (Peak at 24 h after MCAO) levels in the affected cortices of MCAO rats. In the in vitro model, the levels of IL‐6 and pSTAT3 in astrocytes were significantly reduced by treatment with Filgotinib (JAK‐1 inhibitor) but not AG490 (JAK‐2 inhibitor). Moreover, the suppression of IL‐6 expression reduced FD‐induced increases in pSTAT3 and pJAK‐1. In turn, inhibited pSTAT3 expression also depressed the FD‐mediated increase in IL‐6 expression. Conclusions FD led to the overproduction of IL‐6 and subsequently increased pSTAT3 levels via JAK‐1 but not JAK‐2, which further promoted increased IL‐6 expression, thereby exacerbating the inflammatory response of primary astrocytes.

Adjuvant Novel Nanocarrier-Based Targeted Therapy for Lung Cancer

“…Another study found that folic acid deficiency promotes IL-6/JAK-1/pSTAT3 interactions in astrocytes after ischemia-reperfusion. So, folic acid-biofunctionalized nanocarriers may be another approach to improving targeting precision [ 86 ]. Further, the PEGylation of NPs reduces the interaction with serum proteins and enhances the stability of the nanocarrier in the reticuloendothelial system [ 87 ].…”

Potential Role of Natural Antioxidants in Countering Reperfusion Injury in Acute Myocardial Infarction and Ischemic Stroke

“…Folic acid, a type of B vitamin essential in the regular human diet, is strongly associated with neuroinflammation [ 210 ]. It is also key for the development and function of the nervous system [ 86 ] and has been shown to have an antioxidant and a neuroprotective role [ 211 ].…”

“…In addition, another study, using a model of in vivo rats, as well as an oxygen–glucose deprivation/reoxygenation astrocyte cell model, found that in the context of ischemia–reperfusion, folic acid deficiency may develop an inflammatory response via the IL-6/JAK-1/phospho-STAT3 (pSTAT3) pathway on astrocytes, potentially leading to secondary brain injury. Therefore, folic acid supplementation was suggested as a potential preventive and therapeutic strategy to reduce brain damage in IS [ 210 ].…”