Glutamine Administration in Early or Late Septic Phase Downregulates Lymphocyte PD-1/PD-L1 Expression and the Inflammatory Response in Mice With Polymicrobial Sepsis

Abstract

Background: Sepsis is a severe inflammatory response to infection. Excessive compensation to inflammation leads to dysregulated immune response that ultimately results in organ damage and lethality of sepsis. This study administered glutamine (GLN) in the early or late phase of sepsis to investigate its effects on regulating leukocyte programmed cell death 1 (PD-1) and its ligand (programmed cell death ligand 1 [PD-L1]) expression, macrophage function, inflammation, and acute kidney injury in sepsis. Methods: Mice were randomly assigned to cecal ligation and puncture (CLP) or sham-operated groups. Septic mice were respectively injected once with saline or 0.75 g GLN/kg body weight at 3 or 10 hours post-CLP via tail vein. All mice were sacrificed 24 hours after CLP. Results: Sepsis enhanced the percentage of interferon-γ–expressing and interleukin (IL)-17A–expressing CD4⁺ T cells, expression of PD-1 on T cells, and PD-L1 on B cells and monocytes. Inflammatory mediator messenger RNA (mRNA) expression in kidney tissues and proapoptotic caspase-3 mRNA expression in mesenteric lymph nodes were also upregulated. GLN administration decreased plasma IL-6 level, downregulated the percentage of IL-17A–expressing CD4⁺ T cells, attenuated macrophage dysfunction, decreased caspase-3 mRNA expression, and reduced PD-1/PD-L1 expression by T and B cells. Histological findings also showed that kidney damage was attenuated. GLN administered at 3 and 10 hours after CLP offered nearly equal effects on PD-1/PD-L1 and inflammatory mediator expression after CLP. Conclusions: These findings suggest that a single dose of GLN administration in either the early or late phase during sepsis promotes a more balanced immune regulation and reduced systemic and kidney inflammatory responses in mice.