Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling

Gopallawa, Indiwari; Freund, Jenna R.; Lee, Robert J.

doi:10.1101/776344

Cited by 13 publications

(36 citation statements)

References 67 publications

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“…However, in recent years, the discovery of the T2Rs in extraoral tissues has suggested other roles for these receptors beyond taste, including immune surveillance[ 83 ]. A variety of bitter receptors are expressed in the motile cilia in human airway epithelial cells[ 44 ] and macrophages[ 84 ] which are stimulated by bitter molecules such as denatonium benzoate[ 85 ], thujone from the wormwood plant[ 85 ], sodium thiocyanate[ 12 ], phenylthiocarbamide (PTC)[ 12 ], and bitter plant flavonoids[ 25 ]. These T2Rs also recognize gram-negative bacterial products such as acyl-homoserine lactone (AHL)[ 12 ] and quinolone[ 86 ] quorum-sensing molecules, suggesting they may play a role in sensing developing biofilms.…”

Section: Overview Of Respiratory Innate Immunitymentioning

confidence: 99%

“…These high levels of NO can be involved in immune cell killing of bacteria[ 117 ]. In contrast, nNOS and eNOS produce lower levels of NO often associated with cellular signaling pathways that regulate a variety of physiological endpoints like ciliary beating and vascular tone, as described above, and also macrophage phagocytosis[ 84 ]. However, Ca 2+ -dependent activation of eNOS in sinonasal airway epithelial cells can directly kill bacteria like P. aeruginosa in the airway surface liquid[ 12 , 118 ].…”

Section: Downstream Targets Of Akt Involved In Innate Immunity and Inmentioning

confidence: 99%

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Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

Gopallawa¹,

Lee²

2020

WJBC

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The airway innate immune system maintains the first line of defense against respiratory infections. The airway epithelium and associated immune cells protect the respiratory system from inhaled foreign organisms. These cells sense pathogens via activation of receptors like toll-like receptors and taste family 2 receptors (T2Rs) and respond by producing antimicrobials, inflammatory cytokines, and chemokines. Coordinated regulation of fluid secretion and ciliary beating facilitates clearance of pathogens via mucociliary transport. Airway cells also secrete antimicrobial peptides and radicals to directly kill microorganisms and inactivate viruses. The phosphoinositide-3-kinase/protein kinase B (Akt) kinase pathway regulates multiple cellular targets that modulate cell survival and proliferation. Akt also regulates proteins involved in innate immune pathways. Akt phosphorylates endothelial nitric oxide synthase (eNOS) enzymes expressed in airway epithelial cells. Activation of eNOS can have anti-inflammatory, anti-bacterial, and anti-viral roles. Moreover, Akt can increase the activity of the transcription factor nuclear factor erythroid 2 related factor-2 that protects cells from oxidative stress and may limit inflammation. In this review, we summarize the recent findings of non-cancerous functions of Akt signaling in airway innate host defense mechanisms, including an overview of several known downstream targets of Akt involved in innate immunity.

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Section: Overview Of Respiratory Innate Immunitymentioning

confidence: 99%

Section: Downstream Targets Of Akt Involved In Innate Immunity and Inmentioning

confidence: 99%

Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

Gopallawa¹,

Lee²

2020

WJBC

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“…After removal of the trypan blue suspension phagocytosis status was immediately evaluated by fluorescence plate reader at 480 nm excitation, 520 nm emission (Synergy HTX multi-mode reader by BioTeK) (Fig3C-D). (Gopallawa et al 2020) Cell Survival and Apoptosis Assays HMC3 cell viability in response to Aβ42 treatment was determined using MTT (0.5 mg/ml) assay and trypan blue exclusion (TBE). HMC3 cells were cultivated at a density of 10,000 cells/well in 96-well plates for 0, 8 24, 48 and 72 hours.…”

Section: Morphology and Phagocytosis Assaymentioning

confidence: 99%

TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ₄₂in HMC3 cells

Akhter

Shao

Formica

et al. 2020

Preprint

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Alzheimer’s disease (AD) is characterized by the accumulation in the brain of extracellular amyloid β (Aβ) plaques as well as intraneuronal inclusions (neurofibrillary tangles) consisting of total tau and phosphorylated tau. Also present are dystrophic neurites, loss of synapses, neuronal death, and gliosis. AD genetic studies have highlighted the importance of inflammation in this disease by identifying several risk associated immune response genes, including TREM2. TREM2 has been strongly implicated in basic microglia function including, phagocytosis, apoptosis, and the inflammatory response to Aβ in mouse brain and primary cells. These studies show that microglia are key players in the response to Aβ and in the accumulation of AD pathology. However, details are still missing about which apoptotic or inflammatory factors rely on TREM2 in their response to Aβ, especially in human cell lines. Given these previous findings our hypothesis is that TREM2 influences the response to Aβ toxicity by enhancing phagocytosis and inhibiting both the BCL-2 family of apoptotic proteins and pro-inflammatory cytokines. Aβ42 treatment of the human microglial cell line, HMC3 cells, was performed and TREM2 was overexpressed or silenced and the phagocytosis, apoptosis and inflammatory response were evaluated. Results indicate that a robust phagocytic response to Aβ after 24 hours requires TREM2 in HMC3 cells. Also, TREM2 inhibits Aβ induced apoptosis by activating the Mcl-1/Bim complex. TREM2 is involved in activation of IP-10, MIP-1a, and IL-8, while it inhibits FGF-2, VEGF and GRO. Taken together, TREM2 plays a role in enhancing the microglial functional response to Aβ toxicity in HMC3 cells. This novel information suggests that therapeutic strategies that seek to activate TREM2 may not only enhance phagocytosis, but it may also inhibit beneficial inflammatory factors, emphasizing the need to define TREM2-related inflammatory activity in not only mouse models of AD, but also in human AD.

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“…NO can also inhibit the replication of many respiratory viruses, including influenza, parainfluenza, rhinovirus,(37) and SARS-CoV-1 & -2 (38)(39)(40)(41). In macrophages, T2R-stimulated NO production and cGMP production acutely increases phagocytosis (42). Thus, T2R to NO signaling may also be an important therapeutic target in infectious diseases beyond the airway.…”

Section: Introductionmentioning

confidence: 99%

HSP90 modulates T2R bitter taste receptor nitric oxide production and innate immune responses in human airway epithelial cells and macrophages

Carey

Hariri

Adappa

et al. 2021

Preprint

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Bitter taste receptors (T2Rs) are G protein-coupled receptors (GPCRs) expressed in various cell types including ciliated airway epithelial cells and macrophages. T2Rs in these two airway innate immune cell types are activated by bitter products, including those secreted by common airway pathogens like Pseudomonas aeruginosa, leading to Ca2+-dependent activation of endothelial nitric oxide (NO) synthase (eNOS). NO production leads to enhanced mucociliary clearance and direct antibacterial effects by ciliated epithelial cells as well as increased phagocytosis by macrophages. Using biochemistry and live cell imaging, we explored the role of heat shock protein 90 (HSP90) in regulating T2R-dependent NO pathways in primary sinonasal epithelial cells, primary monocyte-derived macrophages, and a human bronchiolar cell line (H441). We used immunofluorescence to show that H441 cells express eNOS and certain T2Rs and that the bitterant denatonium benzoate activates NO production in an HSP90-dependent manner in cells grown either as submerged cultures and at air liquid interface. In primary sinonasal epithelial cells, we determined that HSP-90 inhibition reduces T2R-stimulated NO production and ciliary beating which are crucial for pathogen clearance. In primary monocyte-derived macrophages, we found that HSP-90 is integral to T2R-stimulated NO production and phagocytosis of FITC-labeled Escherichia coli and pHrodo-Staphylococcus aureus. Our study demonstrates that HSP90 serves an innate immune role by regulating NO production downstream of T2R signaling by augmenting eNOS activation without impairing upstream calcium signaling. These findings suggest that HSP90 plays an important role in airway antibacterial innate immunity and may be an important target in airway diseases like chronic rhinosinusitis, asthma, or cystic fibrosis.

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Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling

Cited by 13 publications

References 67 publications

Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ₄₂in HMC3 cells

HSP90 modulates T2R bitter taste receptor nitric oxide production and innate immune responses in human airway epithelial cells and macrophages

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Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling

Cited by 13 publications

References 67 publications

Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42in HMC3 cells

HSP90 modulates T2R bitter taste receptor nitric oxide production and innate immune responses in human airway epithelial cells and macrophages

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TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ₄₂in HMC3 cells