Blockade of IL-17A/IL-17R Pathway Protected Mice from Sepsis-Associated Encephalopathy by Inhibition of Microglia Activation

Abstract

Sepsis-associated encephalopathy (SAE) is a poorly understood condition that leads to long-term cognitive impairment and increased mortality in survivors. Recent research revealed that IL-17A/IL-17R might serve as a checkpoint in microglia-mediated neuroinflammation. The present study was designed to determine the specific role of IL-17A-mediated microglia activation in the development of SAE. A mouse model of SAE was induced by cecal ligation and puncture (CLP), and behavior performance was evaluated by the inhibitory avoidance test and the open field test. Cytokine expression and microglia activation in brain tissue were determined at 6 h, 12 h, 24 h, 48 h, and day 7 post surgery. Further, septic mice were intracerebral ventricle- (i.c.v.-) injected with recombinant IL-17A, anti-IL-17A ab, anti-IL-17R ab, or isotype controls to evaluate the potential effects of IL-17A/IL-17R blockade in the prevention of SAE. Septic peritonitis induced significant impairment of learning memory and exploratory activity, which was associated with a higher expression of IL-17A, IL-1β, and TNF-α in the brain homogenate. Fluorescence intensity of Iba-1 and IL-17R in the hippocampus was significantly increased following CLP. Treatment with recombinant IL-17A enhanced the neuroinflammation and microglia activation in CLP mice. On the contrary, neutralizing anti-IL-17A or anti-IL-17R antibodies mitigated the CNS inflammation and microglia activation, thus alleviating the cognitive dysfunction. Furthermore, as compared to the sham control, microglia cultured from CLP mice produced significantly higher levels of cytokines and expressed with higher fluorescence intensity of Iba-1 in response to IL-17A or LPS. Pretreatment with anti-IL-17R ab suppressed the Iba-1 expression and cytokine production in microglia stimulated by IL-17A. In conclusion, blockade of the IL-17A/IL-17R pathway inhibited microglia activation and neuroinflammation, thereby partially reversing sepsis-induced cognitive impairment. The present study suggested that the IL-17A/IL-17R signaling pathway had an important, nonredundant role in the development of SAE.

Regulation of blood–brain barrier integrity by microglia in health and disease: A therapeutic opportunity

“…100 For example, pharmacological inhibition of IL-17A/IL-17AR signaling with neutralizing antibodies prevented microglial transition to an activated pro-inflammatory state, a mechanism that reduced cognitive impairment in a murine model of sepsis-associated encephalopathy. 101 Interestingly, IL-17A signaling contributes to BBB dysfunction as indicated by decreased claudin-5 and occludin protein expression and increased MMP-2/MMP-9 activity. 102 Astrocytes also participate in a positive feedback loop with microglia that can further exacerbate BBB injury and neuroinflammation.…”

Microglia: A Potential Therapeutic Target for Sepsis-Associated Encephalopathy and Sepsis-Associated Chronic Pain

“…For example, recombinant IL-17A can enhance neuroinflammation and microglial activation in caecal ligation and puncture mice. As expected, neutralizing antibodies against IL-17A or IL-17R can reduce CNS inflammation and microglial activation, thereby reducing cognitive dysfunction (Ye et al, 2019). Plus, several plant-derived substances, such as resveratrol, sophoraflavanone G (SG), attractylone, and β-elemene, have also been shown to inhibit microglial-mediated neuroinflammation and improve memory performance in mice with SAE (Guo et al, 2016;Sui et al, 2016;Pan et al, 2019;Tian et al, 2019).…”

“…Bacterial components stimulate microglia via pattern recognition receptors such as Toll-like receptors (TLR-2, TLR-4, and TLR-9) and nucleotide-binding oligomerization domain-2 (NOD2) (Ye et al, 2019). In addition, it has been verified that cytokines (particularly tumour necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6)), which are generated peripherally during sepsis, transmit signals through the impaired blood-brain barrier (BBB) and activate microglia to modulate neuronal function (van Gool et al, 2010).…”

“…The IL-17A/ IL-17R signaling pathway has also been reported to play an important role in stimulating microglia. The IL-17A/IL-17R signaling pathway facilitates microglial secretion of inflammatory factors, including IL-1β and IL-23, which exacerbate the secretion of IL-17A from immune cells and create a vicious cycle of sustained, amplified inflammation in the brain (Ye et al, 2019).…”

Inducing Experimental Polymicrobial Sepsis by Cecal Ligation and Puncture

“…1A-D). Interestingly, CLP has also been employed to address questions regarding acute lung and brain injury (Singer et al, 2016;Wang et al, 2019;Ye et al, 2019;Yehya et al, 2015), demonstrating that CLP can be used as a tool to address a diverse array of experimental questions. Since the previous publication of the CLP methodology in Current Protocols in Immunology in 2010 (Cuenca, Delano, Kelly-Scumpia, Moldawer, & Efron, 2010), the number of papers published using CLP has doubled ( Fig.…”