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. 2021 Apr 15:8:644957.
doi: 10.3389/fmolb.2021.644957. eCollection 2021.

Succinate Promotes Phagocytosis of Monocytes/Macrophages in Teleost Fish

Dai-Xiao Yang  1   2   3 , Hao Yang  1   2   3 , Yun-Chao Cao  1   2   3 , Ming Jiang  1   2   3 , Jun Zheng  4 , Bo Peng  1   2   3
Affiliations

Succinate Promotes Phagocytosis of Monocytes/Macrophages in Teleost Fish

Dai-Xiao Yang et al. Front Mol Biosci. .

Abstract

Development of immunity-based strategy to manage bacterial infection is urgently needed in aquaculture due to the widespread of antibiotic-resistant bacteria. Phagocytosis serves as the first line defense in innate immunity that engulfs bacteria and restricts their proliferations and invasions. However, the mechanism underlying the regulation of phagocytosis is not fully elucidated and the way to boost phagocytosis is not yet explored. In this manuscript, we profiled the metabolomes of monocytes/macrophages isolated from Nile tilapia, prior and after phagocytosis on Vibrio alginolyticus. Monocytes/macrophages showed a metabolic shift following phagocytosis. Interestingly, succinate was accumulated after phagocytosis and was identified as a crucial biomarker to distinguish before and after phagocytosis. Exogenous succinate increased the phagocytotic rate of monocytes/macrophages in a dose-dependent manner. This effect was dependent on the TCA cycle as the inhibitor of malonate that targets succinate dehydrogenase abrogated the effect. Meanwhile, exogenous succinate regulated the expression of genes associated with innate immune and phagocytosis. In addition, succinate-potentiated phagocytosis was applicable to both gram-negative and -positive cells, including V. alginolyticus, Edwardsiella tarda, Streptococcus agalactiae, and Streptococcus iniae. Our study shed light on the understanding of how modulation on host's metabolism regulates immune response, and this can be a potent therapeutic approach to control bacterial infections in aquaculture.

Keywords: aquatic pathogens; innate immunity; metabolic regulation; monocytes/macrophages; phagocytosis; succinate.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Metabolic profiles of monocytes/macrophages before and following phagocytosis. (A) Schematic representation of experiment workflow; (B) The phagocytosis rate and phagocytic index of monocytes/macrophages. (C) Reliability of metabolomic profiling for the replicates. Pearson correlation coefficient was shown. (D) Functional categories of the metabolites. (E) Heat map of all metabolites (row). Yellow indicates the increase in the abundance of metabolites and blue indicates decrease.
FIGURE 2
FIGURE 2
Metabolic profiling of monocytes/macrophages of O. niloticus before and after phagocytosis. (A) Functional categories of the differential metabolites. (B) Histogram of altered metabolite of each functional category after phagocytosis. (C) Changes of differential metabolites in tilapia head kidney monocytes/macrophages following phagocytosis of bacteria by Wilcoxon, p < 0.01). (D) Z-score plots of differential metabolites of tilapias head kidney monocytes/macrophages following phagocytosis of bacteria.
FIGURE 3
FIGURE 3
Metabolomic alterations at different groups. (A) Pathway enrichment analysis of differential metabolites that were used for visualization. (B) Heat map of differential metabolites. Yellow indicates an increase in metabolites and blue indicates a decrease, which were represented by the average and standard deviation of the metabolite relative abundance. (C) iPath analysis of the differential metabolites.
FIGURE 4
FIGURE 4
Identification of crucial biomarkers before and after phagocytosis. (A) OPLS-DA analysis of metabolic data before and following phagocytosis. Each point represents a technical replicate of the sample. (B) S-plot. p [1] and correlation p(corr) [1] distinguish monocytes/macrophages before and after phagocytosis. (C) Succinate and fumarate were the crucial biomarkers for phagocytosis. (D) ROC curve of biomarkers for phagocytosis. *p < 0.05; **p < 0.01.
FIGURE 5
FIGURE 5
Succinate promotes the phagocytosis of O. niloticus monocytes/macrophages. (A) the monocytes/macrophages were incubated with or without ethyl succinate (20 mM) for 4 h. (B) the monocytes/macrophages were incubated with or without succinate or diethyl malonate treatment for 4 h. (C) the monocytes/macrophages activity of PDH, MDH, KGDH, and SDH. (D) Phagocytosis rate and phagocytic index of FITC-conjugated gram-negative or gram-positive bacteria by succinate-pretreated monocytes/macrophages at indicated concentration. Error bars were represented as means ± SEM from three biological replicates. Statistical significance was obtained when *p < 0.05 or **p < 0.01.
FIGURE 6
FIGURE 6
Gene expression of monocytes/macrophages. qRT-PCR of the immune genes and phagocytic genes before and after phagocytosis. Error bars were represented as means ± SEM from three biological replicates. Statistical significance was obtained when *p < 0.05 or **p < 0.01.
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