Activation of PD-1 Protects Intestinal Immune Defense Through IL-10/miR-155 Pathway After Intestinal Ischemia Reperfusion
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To date, mechanisms of intestinal immunoglobulin (Ig) dysfunction following intestinal ischemia/reperfusion (I/R) remain unclear. Programmed death 1 (PD-1) is associated with immune responses of lymphocytes.
We aimed to verify the hypothesis that activation of PD-1 may improve intestinal immune dysfunction by regulating IL-10/miR-155 production after intestinal IR injury.
Intestinal I/R injury was induced in mice by clamping the superior mesenteric artery for 1 h followed by 2-h reperfusion. PD-L1 fusion Ig, anti-interleukin (IL)-10 monoclonal antibody (mAb), and microRNA (miR)-155 agomir were administered. PD-1 expression, IL-10 mRNA, and protein expression in Peyer’s patches (PP) CD4+ cells were measured. MiR-155 levels, tumor necrosis factor (TNF)-α and IL-1β concentration, and activation-induced cytidine deaminase (AID), a key enzyme for intestinal immune antibodies, in PP tissues were measured, respectively. Importantly, the production and cecal bacteria-binding capacity of IgA and IgM were detected.
Intestinal I/R led to decreased PD-1 expression, imbalanced production, and impaired bacteria-binding capacity of IgA and IgM. Activating PD-1 by PD-L1 Ig facilitated IL-10 synthesis, then decreased miR-155 levels, and subsequently promoted AID expression and reduced TNF-α, IL-1β concentration. Upregulation of AID improved the disruptions of intestinal immune barrier caused by IgA and IgM dysfunction. Anti-IL-10 mAb and miR-155 agomir abolished the protective effects of PD-L1 Ig on the intestinal immune defense.
Activation of PD-1 with PD-L1 Ig relieves intestinal immune defensive injury through IL-10/miR-155 pathway following intestinal I/R attack. PD-1, IL-10, and miR-155 may be potential targets for the damages of intestinal barrier and immunity.
KeywordsIntestinal mucosa Reperfusion injury Programmed cell death 1 receptor microRNA Interleukin-10
The authors thank Jie Li (Laboratory Animal Center, Sun Yat-sen University) for her help in animal experiments.
The present study was supported by Grants from the Natural Science Foundation of Guangdong Province, China (Grant 2017A030313572 to Xu-Yu Zhang) and grants from the National Natural Science Foundation of China (Grant 81701874 to Zi-meng Liu).
Compliance with ethical standards
Conflicts of Interest
The authors declare that they have no conflict of interest.
- 1.Mallick IH, Yang W, Winslet MC, et al. Ischemia-reperfusion injury of the intestine and protective strategies against injury. Dig Dis Sci. 2004;49:1359–1377. https://doi.org/10.1023/B:DDAS.0000042232.98927.91.CrossRefPubMedGoogle Scholar