Alteration of macrophage immune phenotype in a murine sepsis model is associated with susceptibility to secondary fungal infection

Abstract

Background: Secondary fungal infection is a major complication in patients with sepsis-associated immunosuppression. However, sepsis-induced immune alterations related to fungal susceptibility have not been well characterized.Objective: To determine kinetic changes in the immune phenotype by determining the proportion of T cells, B cells and macrophages, and especially the expression of an immune exhaustion marker PD-1, in murine sepsis. In addition, sepsis -induced alterations of these immune cells were assessed in relation to susceptibility to secondary fungal infection.Methods: Cecal ligation and puncture (CLP) was used as a mouse sepsis model, with Candida albicans as the secondary systemic fungal infection. Splenic T cells, B cells and macrophages were assessed by flow cytometry. Results: Alterations in T cell and B cell numbers and the proportion of PD-1 expressing T cells and B cells in CLP micewere not clearly related to susceptibility to secondary Candida infection. By contrast, changes in levels of CD86 + -activated macrophages, and the proportion of the PD-1 + population among the CD86 + macrophages in CLP mice were found to be related to secondary fungal infection susceptibility. Conclusion:Macrophage activation and exhaustion might be a significant determinant in susceptibility to fungal infection, and outcomes of infection. This study provided more comprehensive knowledge pertinent to patient evaluation and therapeutics design in restoring host defenses against secondary fungal infection in those with sepsis.

The emerging roles and therapeutic potential of B cells in sepsis

“…In concert with the findings in human sepsis, the inhibitory receptors, PD-1 and PD-L1, as well as the apoptosis receptor, CD95, were significantly elevated on B cells in response to CLP-induced sepsis ( Tao et al, 2019 ; Umakoshi et al, 2020 ; Vu et al, 2022 ). Interestingly, an improved state of B-cell activation was seen in septic mice by the higher proportion of CD69 + , CD86 + , and MHC-II expressing splenic B cells early after CLP ( Kelly-Scumpia et al, 2011 ; Mohr et al, 2012 ).…”

“…A prominent reduction in B-cell numbers and percentage has also been observed in septic mice (Mohr et al, 2012;Kulkarni et al, 2018;Sjaastad et al, 2018;Tao et al, 2019;Taylor et al, 2020a;Umakoshi et al, 2020;Vu et al, 2022) (Table 3). The B-cell numbers in the blood, spleen and inguinal lymph nodes were significantly reduced 2 days after sepsis induction, decreasing by 11-fold, 2-fold, and 6-fold, respectively, before recovering to sham levels by day 30 (Sjaastad et al, 2018).…”

“…CD1dhi Bregs and IL-10 production, and increased FasL + B cells in severe endotoxic shock mice; the gene level of proinflammatory, anti-inflammatory, and B cellrelated markers were markedly altered Tao et al cell numbers and increased proportions of PD1+B cells until day 12 post-CLP Vu et al (2022). …”

More Prominent Inflammatory Response to Pachyman than to Whole-Glucan Particle and Oat-β-Glucans in Dextran Sulfate-Induced Mucositis Mice and Mouse Injection through Proinflammatory Macrophages

“…In contrast, Oat-BG exhibits an anti-inflammatory effect in some situations (Crohn’s disease, obesity, and vigorous exercise) [ 18 , 19 , 94 , 95 ]. Despite some proinflammatory effects of Oat-BG in our experiments, Oat-BG demonstrated the least inflammatory activity and might be suitable to boost up immune responses [ 96 , 97 , 98 , 99 ], induce trained immunity (innate immune memory, the increased innate immune responses after the subsequent activation) [ 100 ], or improve gut dysbiosis [ 101 , 102 , 103 ]. The high viscosity (gelation-liked property) of Oat-BG (and other BG from plant grains) [ 52 ] may prevent gut translocation; increase intestinal viscosity; and thereby improve glucose–lipid homeostasis (delayed glucose absorption, decreased bile acid absorption, increased bile acid excretion, and enhanced hepatic cholesterol metabolism) [ 52 ].…”

The Role of Immune Checkpoint Molecules on Macrophages in Cancer, Infection, and Autoimmune Pathologies

“…On day 1 post-CLP, the levels of PD-1 + macrophages are significantly increased, while presenting an exhausted immune phenotype similar to the M2 profile. Besides that, activated macrophages in an M1-like phenotype can only be found on day 12 post-CLP when PD-1 expression is low ( 91 ). This confirms a correlation between PD-1 overexpression and M2 macrophage phenotype in sepsis as previously suspected.…”