Abstract
BackgroundAn innate immune memory response can manifest in two ways: immune training and immune tolerance, which refers to an enhanced or suppressed immune response to a second challenge, respectively. Exposing monocytes to moderate-to-high amounts of bacterial lipopolysaccharide (LPS) induces immune tolerance, whereas fungal β-glucan (BG) induces immune training. In microglia, it has been shown that different LPS inocula in vivo can induce either immune training or tolerance. Few studies focused on impact of BG on microglia and were only performed in vitro. The aim of the current study was to determine whether BG activates and induces immune memory in microglia upon peripheral administration in vivo.MethodsTwo experimental designs were used. In the acute design, mice received an intraperitoneal (i.p.) injection with PBS, 1 mg/kg LPS or 20 mg/kg BG and were terminated after 3 h, 1 or 2 days. In the preconditioning design, animals were first challenged i.p. with PBS, 1 mg/kg LPS or 20 mg/kg BG. After 2, 7 or 14 days, mice received a second injection with PBS or 1 mg/kg LPS and were sacrificed 3 h later. Microglia were isolated by fluorescence-activated cell sorting, and cytokine gene expression levels were determined. In addition, a self-developed program was used to analyze microglia morphological changes. Cytokine concentrations in serum were determined by a cytokine array.ResultsMicroglia exhibited a classical inflammatory response to LPS, showing significant upregulation of Tnf, Il6, Il1β, Ccl2, Ccl3 and Csf1 expression, three h after injection, and obvious morphological changes 1 and 2 days after injection. With an interval of 2 days between two challenges, both BG and LPS induced immune training in microglia. The training effect of LPS changed into immune tolerance after a 7-day interval between 2 LPS challenges. Preconditioning with BG and LPS resulted in increased morphological changes in microglia in response to a systemic LPS challenge compared to naïve microglia.ConclusionsOur results demonstrate that preconditioning with BG and LPS both induced immune training of microglia at two days after the first challenge. However, with an interval of 7 days between the first and second challenge, LPS-preconditioning resulted in immune tolerance in microglia.
Highlights
An innate immune memory response can manifest in two ways: immune training and immune tolerance, which refers to an enhanced or suppressed immune response to a second challenge, respectively
Stimulation of BV-2 luciferase cells with 100 ng/ mL LPS resulted in significantly increased luciferase activity after 30 min which peaked around 4 h (Additional file 3a). 10 μg/mL BG activated nuclear factor-κB (NF-κB) signaling within 2 h and peaked around 6 h after stimulation (Additional file 3a)
Primary microglia were stimulated with LPS or BG, and after 3 hr, mRNA levels were quantified using room temperature (RT)-Quantitative RT-PCR (qPCR)
Summary
An innate immune memory response can manifest in two ways: immune training and immune tolerance, which refers to an enhanced or suppressed immune response to a second challenge, respectively. It has been shown that different LPS inocula in vivo can induce either immune training or tolerance. It has become evident that in partial analogy to adaptive immune cells, innate immune cells, like monocytes and macrophages, can acquire immune memory. Innate immune memory can manifest in two different ways, immune training and immune tolerance, which means an enhanced or suppressed immune response towards a secondary challenge. Lipopolysaccharide (LPS) and β-glucan (BG) are two commonly used ligands to induce immune tolerance and training in monocytes/macrophages, respectively. Mice preconditioned with a super-low dose (5 ng/kg body weight) of LPS displayed exacerbated sepsis-induced tissue damage, bacterial load in circulation, and mortality [17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
