Lactate-Dependent Regulation of Immune Responses by Dendritic Cells and Macrophages

Manoharan, Indumathi; Prasad, Puttur D.; Thangaraju, Muthusamy; Manicassamy, Santhakumar

doi:10.3389/fimmu.2021.691134

Cited by 85 publications

(59 citation statements)

References 165 publications

(342 reference statements)

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“…Lactate treatment also upregulated M2-associated genes and markers by a mechanism dependent on HIF-1α [ 51 ]. Recent studies have suggested that lactate may serve as a feedback signal that limits excessive inflammatory response by interfering with cellular metabolism [ 52 , 53 ]. Selleri et al reported that lactate induced dose-dependent preferential monocyte differentiation into M2 macrophages by metabolic reprogramming [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

et al. 2022

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Background Effective removal of pathogenic bacteria is key to improving the prognosis of sepsis. Polymorphonuclear neutrophils (PMNs) are the most important components of innate cellular immunity and play vital roles in clearing pathogenic bacteria. However, the metabolic characteristics and immunomodulatory pathways of PMNs during sepsis have not been investigated. In the present study, we explored the immune metabolism characteristics of PMNs and the mechanism by which neutrophilic glycolysis is regulated during sepsis. Methods Metabolomics analysis was performed on PMNs isolated from 14 septic patients, 26 patients with acute appendicitis, and 19 healthy volunteers. Transcriptome analysis was performed on the PMNs isolated from the healthy volunteers and the patients with sepsis to assess glycolysis and investigate its mechanism. Lipopolysaccharide (LPS) was used to stimulate the neutrophils isolated from the healthy volunteers at different time intervals to build an LPS-tolerant model. Chemotaxis, phagocytosis, lactate production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) were evaluated. Results Transcriptomics showed significant changes in glycolysis and the mTOR/HIF-1α signaling pathway during sepsis. Metabolomics revealed that the Warburg effect was significantly altered in the patients with sepsis. We discovered that glycolysis regulated PMNs’ chemotaxis and phagocytosis functions during sepsis. Lactate dehydrogenase A (LDHA) downregulation was a key factor in the inhibition of glycolysis in PMNs. This study confirmed that the PI3K/Akt-HIF-1α pathway was involved in the LDHA expression level and also influenced PMNs’ chemotaxis and phagocytosis functions. Conclusions The inhibition of glycolysis contributed to neutrophil immunosuppression during sepsis and might be controlled by PI3K/Akt-HIF-1α pathway-mediated LDHA downregulation. Our study provides a scientific theoretical basis for the management and treatment of patients with sepsis and promotes to identify therapeutic target for the improvement of immune function in sepsis.

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Section: Discussionmentioning

confidence: 99%

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

et al. 2022

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“…As previously stated, PDAC has multiple subtypes, each with a varied response to different treatments. In fact, the basal subtype is shown to have an altered metabolism favouring glycolysis (Daemen et al, 2015) and a high lactate content in these tumors might impair the immune response and cause treatment resistance (Husain et al, 2013;Manoharan et al, 2021). Hence, these factors should be included in the 3D model systems used for identification of novel drug sensitivities and resistance mechanisms in PDAC.…”

Section: Discussionmentioning

confidence: 99%

PDAC as an Immune Evasive Disease: Can 3D Model Systems Aid to Tackle This Clinical Problem?

Narayanan

Vicent

Ponz-Sarvisé

2021

Front. Cell Dev. Biol.

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a high mortality rate. The presence of a dense desmoplastic stroma rich in fibroblasts, extracellular matrix, and immune cells plays a critical role in disease progression, therapy response and is a distinguishing feature of PDAC. PDAC is currently treated with a combination of surgery, chemotherapy and radiation therapy in selected cases which results in long-term survival only in a small percentage of patients. Cancer therapies that incorporate immunotherapy-based techniques have become increasingly common in recent years. While such a strategy has been shown to be effective for immunogenic, “hot” tumors like melanoma and lung cancer, thus far PDAC patients display poor responses to this therapeutic approach. Various factors, such as low tumor mutational burden, increased infiltration of immunosuppressive cells, like MDSCs and Treg cells promote tolerance and immune deviation, further aggravating adaptive immunity in PDAC. In this review we will elaborate on the ability of PDAC tumors to evade immune detection. We will also discuss various 3D model system that can be used as a platform in preclinical research to investigate rational combinations of immunotherapy with chemotherapy or targeted therapy, to prime the immune microenvironment to enhance antitumor activity.

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“…Previous in vitro study indicated free radical scavenging and antioxidant effects of lactate [43]. Recent studies have suggested that lactate exhibits an inflammatory or anti-inflammatory role depending on its effects on immune cell types and disease types [44]. Thus, the implication of lactate accumulation in the AL and AP groups remains to be explored.…”

Section: Organic Acidsmentioning

confidence: 99%

Supplemental Aspergillus Lipase and Protease Preparations Display Powerful Bifidogenic Effects and Modulate the Gut Microbiota Community of Rats

et al. 2021

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Aspergillus-derived protease and lipase, which are involved in the production of Aspergillus-fermented foods, are consumed as digestive enzyme supplements. A marked bifidogenic effect of supplemental Aspergillus protease preparation (AP) in rats fed with a high-fat diet was identified. This study was conducted to examine whether the consumption of Aspergillus-derived lipase exerts similar bifidogenic effect. Rats were fed diets supplemented with either an Aspergillus-derived lipase preparation (AL) or AP at 0.1% for two weeks. 16S rRNA gene sequencing analysis indicated that supplemental AL and AP markedly influenced cecal microbial community. At the phylum level, treatment with AL and AP resulted in a lower relative abundance of Firmicutes and Bacteroidetes, but a higher relative abundance of Actinobacteria and Proteobacteria than the control rats (p < 0.05). At the genus level, AL and AP remarkedly elevated the relative abundances of Bifidobacterium, Collinsella, and Enterococcus, but significantly reduced those of Oscillospira, Dorea, and Coprobacillus (p < 0.05). These modulations were similar to those reported by several studies with typical prebiotic oligosaccharides. Notably, the bifidogenic effect of AL was much greater than that of AP. Our results show that the two different Aspergillus-derived preparations, AL and AP, have strong bifidogenic effects and can change the microbiota’s composition.

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Lactate-Dependent Regulation of Immune Responses by Dendritic Cells and Macrophages

Cited by 85 publications

References 165 publications

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

PDAC as an Immune Evasive Disease: Can 3D Model Systems Aid to Tackle This Clinical Problem?

Supplemental Aspergillus Lipase and Protease Preparations Display Powerful Bifidogenic Effects and Modulate the Gut Microbiota Community of Rats

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