Acetate moderately attenuates the generation of neutrophil extracellular traps

Ohbuchi, Ayako; Kono, Mari; Takenokuchi, Mariko; Imoto, Shuhei; Saigo, Katsuyasu

doi:10.5045/br.2018.53.2.177

Cited by 9 publications

(4 citation statements)

References 16 publications

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“…Ohbuchi in 2018 showed that acetic acid alone does not induce NET formation in vitro; in fact, acetic acid was capable of moderately inhibiting the formation of NET induced by phorbol 12-myristate 13-acetate (PMA). 45 It appears that this study finding contradicts with our results; however, they used 5% inactivated autologous serum for the incubation of neutrophil and RPMI as the culture medium. In our study, RPMI spontaneously produced NETs (data not shown), as reported by Kamoshida, 2017.…”

Section: Discussioncontrasting

confidence: 94%

Physiological concentrations of short-chain fatty acids induce the formation of neutrophil extracellular traps in vitro

Íñiguez-Gutiérrez

Godínez-Méndez

Fafutis‐Morris

et al. 2020

Int J Immunopathol Pharmacol

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Neutrophils represent the first line of host cellular defense against various pathogens. The most recently described microbicidal mechanism of these cells is the release of neutrophil extracellular traps (NET). Currently, a wide range of chemical and biological stimuli are known to induce this response; however, the effect of short-chain fatty acids (SCFAs) on the induction of NET is still unknown. SCFAs are produced mainly by bacterial fermentation of dietary fiber and are found in host tissues and blood. This study aimed to determine whether physiological levels of SCFAs can induce the formation of NET. Previously reported concentrations of SCFAs (as found in the colonic lumen and peripheral blood in postprandial and basal states) were used to stimulate the neutrophils. In order to determine the signaling pathway utilized by SCFAs, we tested the inhibition of the Free Fatty Acid 2 Receptor (FFA2R) expressed in neutrophils using CATPB, the inhibitor of FFA2R, genistein, an inhibitor of the downstream Gα/q11 proteins and DPI, an inhibitor of the NADPH oxidase complex. The SCFAs at colonic intestinal lumen concentrations were able to induce the formation of NET, and when tested at concentrations found in the peripheral blood, only acetic acid at 100 μM (fasting equivalent) and 700 μM (postprandial equivalent) was found to induce the formation of NET. The administration of the competitive inhibitor against the receptor or blockade of relevant G protein signaling and the inhibition of NADPH oxidase complex decreased NET release. SCFAs stimulate NET formation in vitro and this effect is mediated, in part, by the FFA2R.

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Section: Discussioncontrasting

confidence: 94%

Physiological concentrations of short-chain fatty acids induce the formation of neutrophil extracellular traps in vitro

Íñiguez-Gutiérrez

Godínez-Méndez

Fafutis‐Morris

et al. 2020

Int J Immunopathol Pharmacol

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“…On the contrary, PMA-induced formation of NETs was indeed weakened by butyrate ( Figure 4e,f ), consistent with previous study showing that SCFAs attenuate the generation of NETs. 26 …”

Section: Resultsmentioning

confidence: 99%

Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease

et al. 2021

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Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. We sought to investigate the effects of butyrate on IBD neutrophils and elucidate the therapeutic potential in regulating mucosal inflammation. Peripheral neutrophils were isolated from IBD patients and healthy donors, and profiles of proinflammatory cytokines and chemokines were determined by qRT-PCR and ELISA, respectively. The migration and release of neutrophil extracellular traps (NETs) were studied by a Transwell model and immunofluorescence, respectively. The in vivo role of butyrate in regulating IBD neutrophils was evaluated in a DSS-induced colitis model in mice. We found that butyrate significantly inhibited IBD neutrophils to produce proinflammatory cytokines, chemokines, and calprotectins. Blockade of GPCR signaling with pertussis toxin (PTX) did not interfere the effects whereas pan-histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) effectively mimicked the role of butyrate. Furthermore, in vitro studies confirmed that butyrate suppressed neutrophil migration and formation of NETs from both CD and UC patients. RNA sequencing analysis revealed that the immunomodulatory effects of butyrate on IBD neutrophils were involved in leukocyte activation, regulation of innate immune response and response to oxidative stress. Consistently, oral administration of butyrate markedly ameliorated mucosal inflammation in DSS-induced murine colitis through inhibition of neutrophil-associated immune responses such as proinflammatory mediators and NET formation. Our data thus reveal that butyrate constrains neutrophil functions and may serve as a novel therapeutic potential in the treatment of IBD.

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“…This study demonstrated that neutrophils utilize FAS to build membranes during differentiation or to replenish decayed membranes during inflammatory conditions. Previous studies also reported the influence of SCFAs on effector functions of neutrophils such as apoptosis ( 22 ), ROS generation ( 25 ), chemotaxis ( 26 27 28 ), and NETs formation ( 29 30 ). However, this influence depends on histone deacetylase inhibition ( 31 ), extracellular acidification ( 30 32 ), and specific receptors for SCFAs ( 25 ), rather than on the fatty acid metabolism.…”

Section: Basic Metabolic Pathways In Neutrophilsmentioning

confidence: 90%