Artesunate interacts with Vitamin D receptor to reverse mouse model of sepsis-induced immunosuppression via enhancing autophagy

Abstract

Background and PurposeImmunosuppression is the predominant cause of mortality for sepsis due to failure to eradicate invading pathogens. Unfortunately, no effective and specific drugs capable of reversing immunosuppression are available for clinical use. Increasing evidence implicates vitamin D receptor (VDR) involved in sepsis-induced immunosuppression. Herein, artesunate (AS) was discovered to reverse sepsis-induced immunosuppression and its molecular mechanism is investigated.Experimental ApproachEffect of artesunate on sepsis-induced immunosuppression was investigated in mice and in vitro. VDR was predicted to be an interacted candidate of AS by bioinformatics predict, then identified using PCR and immunoblotting. VDR, ATG16L1 and NF-κB p65 were modified to investigate the alteration of AS’s effect on pro-inflammatory cytokines release, bacteria clearance and autophagy activities in sepsis-induced immunosuppression.Key ResultsAS significantly reduced the mortality of cecal ligation and puncture (CLP)-induced sepsis immunosuppression mice challenged with Pseudomonas Aeruginosa, and enhanced proinflammatory cytokines release and bacterial clearance to reverse sepsis-induced immunosuppression in vivo and in vitro. Mechanically, AS interacted with VDR thereby inhibited the nuclear translocation of VDR, then influencing ATG16L1 transcription and subsequent autophagy activity. In addition, AS inhibited physical interaction between VDR and NF-κB p65 in LPS tolerance macrophages, then promoted nuclear translocation of NF-κB p65, which activated the transcription of NF-κB p65 target genes such as pro-inflammatory cytokines.Conclusion and ImplicationsOur findings provide an evidence that AS interacted with VDR to reverse sepsis-induced immunosuppression in an autophagy and NF-κB dependent way, highlighting a novel approach for sepsis treatment and drug repurposing of AS in the future.

Artesunate protects immunosuppression mice induced by glucocorticoids via enhancing pro-inflammatory cytokines release and bacterial clearance

“…In theory, it is reliably to investigate immunomodulatory agents to improve immune functions based on the molecular mechanism of the immunosuppression of GCs ( Cain and Cidlowski, 2017 ). Previously, in our lab AS was found not only inhibit excessive inflammation during sepsis ( Kuang et al, 2018 ) but also possess an immunomodulatory effect on CLP-induced immunosuppression mice ( Shang et al, 2020 ). Herein, in HC mice, our results further demonstrated AS has a significant protective effect on HC mice via increasing pro-inflammatory cytokines release and enhancing bacterial clearance, suggesting AS is indeed a bidirectional immunomodulator, which is worthy of further investigation.…”

“…Artesunate (AS), an anti-malarial drug, has been discovered to possess an immunomodulatory effect on cecum ligation and puncture (CLP)-induced immunosuppression mice ( Shang et al, 2020 ). However, it is unclear whether AS has potent regulation on GCs-induced immunosuppression.…”

New Insights into Artesunate as a Pleiotropic Regulator of Innate and Adaptive Immune Cells

“…Artesunate could restore Unc-51-like autophagy-activated kinase 1-(ULK1-) mediated autophagy, reverse LPS tolerance, and relieve the immunosuppression of macrophages induced by sepsis. The interference of the CaMKII-IP3R-CaMKKβ pathway [20] and the activation of vitamin D receptor [21] were found involved in the process.…”

“…The neutrophil counts were significantly increased in the blood of mice exposed to low-dose artesunate (8 mg/kg/d) for 45 days [12], suggesting the effect of artesunate on neutrophils is in an immune state-, dosage-, and time-dependent manner, whose specific mechanism remains to be investigated in the future. [8,9] Reduction of proinflammatory cytokines [9] Inhibition of chemotaxis [10] Promotion of oxidative response with infection [11] Promotion of counts with low dose for long time [12] Nrf2 signaling pathway [8] Monoarthritis [7] Allergic asthma [8] Septic lung injury [9] Monocytes/ macrophages Reduction of proinflammatory cytokines [13][14][15][16] Reduction of MMP-9 [17] Reduction of NO [18] Inhibition of autophagic activation [19] Promotion of LPS internalization [16] Restoration of autophagy and reversing LPS tolerance in sepsis [20,21] Activation of vitamin D receptor [21] NF-κB pathway [13][14][15]17] cAMP-mediated pathway [18] Wnt/β-catenin pathway [18] TRAF6-Beclinl-PI3KC3 pathway [19] CaMKII-IP3R-CaMKKβ pathway [20] Sepsis [13,14,16,17,20,21] Colitis [15] NK cells Promotion of cytotoxic activity against tumor cells [22][23][24][25]…”

The immunosuppressive activity of artemisinin‐type drugs towards inflammatory and autoimmune diseases

“…Whereas the vast majority of investigations reported on the immunosuppressive effects of artemisinin-type drugs, there are also some studies that observed an increase of immune function, for example, by the inhibitory activity against Treg cells, the recovery of the Th1/Th2 balance, and so on. [243][244][245][246][247] This might be beneficial in cancer treatment, but counterproductive to treat inflammatory and autoimmune diseases. Here, immunosuppressive rather than immune-stimulating effects are required.…”