Fatty acids as modulators of neutrophil recruitment, function and survival

Rodrigues, Hosana Gomes; Sato, Fábio Takeo; Curi, Rui; Vinolo, Marco Aurélio Ramirez

doi:10.1016/j.ejphar.2015.03.098

Cited by 89 publications

(72 citation statements)

References 107 publications

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“…The presence of FFA2 has been reported in cells of the innate immune system, where its expression is particularly marked in neutrophils (33–35). In these cells, FFA2 plays a role in chemotaxis, with a mechanism that seems to be PTX-sensitive, at least in mouse-derived neutrophils (36).…”

Section: Resultsmentioning

confidence: 99%

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

Bolognini

Moss

Nilsson

et al. 2016

Journal of Biological Chemistry

104

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The short chain fatty acid receptor FFA2 is able to stimulate signaling via both Gi- and Gq/G11-promoted pathways. These pathways are believed to control distinct physiological end points but FFA2 receptor ligands appropriate to test this hypothesis have been lacking. Herein, we characterize AZ1729, a novel FFA2 regulator that acts as a direct allosteric agonist and as a positive allosteric modulator, increasing the activity of the endogenously produced short chain fatty acid propionate in Gi-mediated pathways, but not at those transduced by Gq/G11. Using AZ1729 in combination with direct inhibitors of Gi and Gq/G11 family G proteins demonstrated that although both arms contribute to propionate-mediated regulation of phospho-ERK1/2 MAP kinase signaling in FFA2-expressing 293 cells, the Gq/G11-mediated pathway is predominant. We extend these studies by employing AZ1729 to dissect physiological FFA2 signaling pathways. The capacity of AZ1729 to act at FFA2 receptors to inhibit β-adrenoreceptor agonist-promoted lipolysis in primary mouse adipocytes and to promote chemotaxis of isolated human neutrophils confirmed these as FFA2 processes mediated by Gi signaling, whereas, in concert with blockade by the Gq/G11 inhibitor FR900359, the inability of AZ1729 to mimic or regulate propionate-mediated release of GLP-1 from mouse colonic preparations defined this physiological response as an end point transduced via activation of Gq/G11.

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Section: Resultsmentioning

confidence: 99%

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

Bolognini

Moss

Nilsson

et al. 2016

Journal of Biological Chemistry

104

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“…Short‐chain fatty acids induce neutrophil chemotaxis under noninflammatory conditions (Le Poul et al, ; Maslowski et al, ; Sina et al, ; Vinolo et al, ; Vinolo, Ferguson et al, 2011). However, in the presence of chemokines or inflammation, this scenario is less clear (Rodrigues, Takeo Sato, Curi, & Vinolo, ). In the infection model used in this study, we found that the total number of cells within the chamber drastically increases over time, with a peak after 24 hr of the bacteria inoculation.…”

Section: Discussionmentioning

confidence: 99%

Bacterial short-chain fatty acid metabolites modulate the inflammatory response against infectious bacteria

Corrêa

Vieira

Sernaglia

et al. 2017

Cellular Microbiology

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Short-chain fatty acids (SCFAs), predominantly acetic, propionic, and butyric acids, are bacterial metabolites with an important role in the maintenance of homeostasis due to their metabolic and immunomodulatory actions. Some evidence suggests that they may also be relevant during infections. Therefore, we aimed to investigate the effects of SCFAs in the effector functions of neutrophils to an opportunistic pathogenic bacterium, Aggregatibacter actinomycetemcomitans. Using a subcutaneous model to generate a mono, isolated infection of A. actinomycetemcomitans, we demonstrated that the presence of the SCFAs in situ did not affect leukocyte accumulation but altered the effector mechanisms of migrating neutrophils by downregulating the production of cytokines, their phagocytic capacity, and killing the bacteria, thus impairing the containment of A. actinomycetemcomitans. Similar effects were observed with bacteria-stimulated neutrophils incubated with SCFAs in vitro. These effects were independent of free-fatty acid receptor 2 (FFAR2) activation, the main SCFA receptor expressed on neutrophils, occurring possibly through inhibition of histone deacetylases because similar effects were obtained by using histone deacetylase inhibitors, such as SAHA, MS-275, and RGFP 966. Considering the findings of this study, we hypothesized that in an infectious condition, SCFAs may exert a detrimental effect on the host by inhibiting neutrophil's effector functions.

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“…SCFAs interact with neutrophils and modulate their recruitment, effector function and survival at different tissues (reviewed in Rodrigues et al 33 ). These bacterial metabolites alter neutrophils recruitment by their ability to regulate the production of inflammatory mediators including cytokines that activate endothelial cells such as TNF‐α and IL‐17 and neutrophil‐chemoattractants such as CXCL1 and CXCL8 by different cells 26 , 28 , 29 , 30 , 34 , 35 .…”

Section: Neutrophilsmentioning

confidence: 99%

Regulation of immune cell function by short‐chain fatty acids

et al. 2016

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Short-chain fatty acids (SCFAs) are bacterial fermentation products, which are chemically composed by a carboxylic acid moiety and a small hydrocarbon chain. Among them, acetic, propionic and butyric acids are the most studied, presenting, respectively, two, three and four carbons in their chemical structure. These metabolites are found in high concentrations in the intestinal tract, from where they are uptaken by intestinal epithelial cells (IECs). The SCFAs are partially used as a source of ATP by these cells. In addition, these molecules act as a link between the microbiota and the immune system by modulating different aspects of IECs and leukocytes development, survival and function through activation of G protein coupled receptors (FFAR2, FFAR3, GPR109a and Olfr78) and by modulation of the activity of enzymes and transcription factors including the histone acetyltransferase and deacetylase and the hypoxia-inducible factor. Considering that, it is not a surprise, the fact that these molecules and/or their targets are suggested to have an important role in the maintenance of intestinal homeostasis and that changes in components of this system are associated with pathological conditions including inflammatory bowel disease, obesity and others. The aim of this review is to present a clear and updated description of the effects of the SCFAs derived from bacteria on host immune system, as well as the molecular mechanisms involved on them.

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Fatty acids as modulators of neutrophil recruitment, function and survival

Cited by 89 publications

References 107 publications

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

Bacterial short-chain fatty acid metabolites modulate the inflammatory response against infectious bacteria

Regulation of immune cell function by short‐chain fatty acids

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