Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation

Bhatt, Brinda; Zeng, Peng; Zhu, Huabin; Sivaprakasam, Sathish; Li, Siyi; Xiao, Haiyan; Dong, Longlong; Shiao, Pamela; Kolhe, Ravindra; Patel, Nikhil; Li, Honglin; Levy-Bercowski, Daniel; Ganapathy, Vadivel; Singh, Nagendra

doi:10.4049/jimmunol.1701625

Cited by 60 publications

(58 citation statements)

References 63 publications

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“…Therefore, we isolated and cultured primary BMECs from dairy cows for subsequent experiments. GPR109A belongs to the G protein-coupled receptor family [30], which binds chemicals from the surrounding cellular environment and activates a series of signaling pathways within cells [31,32]. Studies have shown that GPR109A is highly expressed in neutrophils [33], macrophages and adipocytes [34].…”

Section: Discussionmentioning

confidence: 99%

Niacin Alleviates Dairy Cow Mastitis by Regulating the GPR109A/AMPK/NRF2 Signaling Pathway

Guo

Liu

et al. 2020

IJMS

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Mastitis is one of three bovine diseases recognized as a cause of substantial economic losses every year throughout the world. Niacin is an important feed additive that is used extensively for dairy cow nutrition. However, the mechanism by which niacin acts on mastitis is not clear. The aim of this study is to investigate the mechanism of niacin in alleviating the inflammatory response of mammary epithelial cells and in anti-mastitis. Mammary glands, milk, and blood samples were collected from mastitis cows not treated with niacin (n = 3) and treated with niacin (30 g/d, n = 3) and healthy cows (n = 3). The expression of GPR109A, IL-6, IL-1β, and TNF-α in the mammary glands of the dairy cows with mastitis was significantly higher than it was in the glands of the healthy dairy cows. We also conducted animal experiments in vivo by feeding rumen-bypassed niacin. Compared with those in the untreated mastitis group, the somatic cell counts (SCCs) and the expression of IL-6, IL-1β, and TNF-α in the blood and milk were lower. In vitro, we isolated the primary bovine mammary epithelial cells (BMECs) from the mammary glands of the healthy cows. The mRNA levels of IL-6, IL-1β, TNF-α, and autophagy-related genes were detected after adding niacin, shRNA, compound C, trans retinoic acid, 3-methyladenine to BMECs. Then GPR109A, AMPK, NRF-2, and autophagy-related proteins were detected by Western blot. We found that niacin can activate GPR109A and phosphorylate AMPK, and promote NRF-2 nuclear import and autophagy to alleviate LPS-induced inflammatory response in BMECs. In summary, we found that niacin can reduce the inflammatory response of BMECs through GPR109A/AMPK/NRF-2/autophagy. We also preliminarily explored the alleviative effect of niacin on mastitis in dairy cows.

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Section: Discussionmentioning

confidence: 99%

Niacin Alleviates Dairy Cow Mastitis by Regulating the GPR109A/AMPK/NRF2 Signaling Pathway

Guo

Liu

et al. 2020

IJMS

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“…SCFA can signal via multiple G-coupled protein receptors, as well as via histone deacetylase enzymes (HDAC) (43), and despite these advances the mechanisms through which SCFA regulate ILC3 are still being delineated. The SCFA receptor GPR109a was implicated in the microbiota-associated regulation of ILC3 cytokine production via the modulation of dendritic cell (DC)-derived IL-23 in the colon, although these studies largely utilized a GPR109a agonist-leaving the precise contribution of endogenous SCFA unclear (45). Interestingly, a recent study highlighted ILC3-intrinsic expression of the SCFA receptor Gpr43 (Ffar2) in the modulation of intestinal ILC3 responses (Figure 1: inputs) (46).…”

Section: Host-microbiota Sensory Circuitsmentioning

confidence: 99%

Immunoregulatory Sensory Circuits in Group 3 Innate Lymphoid Cell (ILC3) Function and Tissue Homeostasis

Domingues

Hepworth

2020

Front. Immunol.

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Recent years have seen a revolution in our understanding of how cells of the immune system are modulated and regulated not only via complex interactions with other immune cells, but also through a range of potent inputs derived from diverse and varied biological systems. Within complex tissue environments, such as the gastrointestinal tract and lung, these systems act to orchestrate and temporally align immune responses, regulate cellular function, and ensure tissue homeostasis and protective immunity. Group 3 Innate Lymphoid Cells (ILC3s) are key sentinels of barrier tissue homeostasis and critical regulators of host-commensal mutualism-and respond rapidly to damage, inflammation and infection to restore tissue health. Recent findings place ILC3s as strategic integrators of environmental signals. As a consequence, ILC3s are ideally positioned to detect perturbations in cues derived from the environment-such as the diet and microbiota-as well as signals produced by the host nervous, endocrine and circadian systems. Together these cues act in concert to induce ILC3 effector function, and form critical sensory circuits that continually function to reinforce tissue homeostasis. In this review we will take a holistic, organismal view of ILC3 biology and explore the tissue sensory circuits that regulate ILC3 function and align ILC3 responses with changes within the intestinal environment.

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“…These benefices in intestinal inflammatory conditions such as inflammatory bowel diseases (IBD) have been demonstrated by Singh et al [ 66 ] that showed the anti-inflammatory properties of GPR109A signaling in colonic macrophages and dendritic cells, enabling them to induce differentiation of Treg cells and IL-10-producing T cells. In this way, pharmacological treatment with niacin improves colitis conditions in a GPR109A-dependent manner [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Potential of Cow, Donkey and Goat Milk Extracellular Vesicles as Revealed by Metabolomic Profile

et al. 2020

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In recent years, extracellular vesicles (EVs), cell-derived micro and nano-sized structures enclosed in a double-layer membrane, have been in the spotlight for their high potential in diagnostic and therapeutic applications. Indeed, they act as signal mediators between cells and/or tissues through different mechanisms involving their complex cargo and exert a number of biological effects depending upon EVs subtype and cell source. Being produced by almost all cell types, they are found in every biological fluid including milk. Milk EVs (MEVs) can enter the intestinal cells by endocytosis and protect their labile cargos against harsh conditions in the intestinal tract. In this study, we performed a metabolomic analysis of MEVs, from three different species (i.e., bovine, goat and donkey) by mass spectroscopy (MS) coupled with Ultrahigh-performance liquid chromatography (UHPLC). Metabolites, both common or specific of a species, were identified and enriched metabolic pathways were investigated, with the final aim to evaluate their anti-inflammatory and immunomodulatory properties in view of prospective applications as a nutraceutical in inflammatory conditions. In particular, metabolites transported by MEVs are involved in common pathways among the three species. These metabolites, such as arginine, asparagine, glutathione and lysine, show immunomodulating effects. Moreover, MEVs in goat milk showed a greater number of enriched metabolic pathways as compared to the other kinds of milk.

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Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation

Cited by 60 publications

References 63 publications

Niacin Alleviates Dairy Cow Mastitis by Regulating the GPR109A/AMPK/NRF2 Signaling Pathway

Niacin Alleviates Dairy Cow Mastitis by Regulating the GPR109A/AMPK/NRF2 Signaling Pathway

Immunoregulatory Sensory Circuits in Group 3 Innate Lymphoid Cell (ILC3) Function and Tissue Homeostasis

Anti-Inflammatory Potential of Cow, Donkey and Goat Milk Extracellular Vesicles as Revealed by Metabolomic Profile

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