Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats

Karuppagounder, Vengadeshprabhu; Bajpai, Anamika; Meng, Shu Zhen; Arumugam, Somasundaram; Sreedhar, Remya; Giridharan, Vijayasree V.; Guha, Ashrith; Bhimaraj, Arvind; Youker, Keith A.; Palaniyandi, Suresh S.; Karmouty‐Quintana, Harry; Kamal, Fadia; Spiller, Kara L.; Watanabe, Kenichi; Thandavarayan, Rajarajan Amirthalingam

doi:10.1371/journal.pone.0200697

Cited by 12 publications

(8 citation statements)

References 31 publications

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“…In our previous work, however, we demonstrated that gallein exhibited no detectable toxicity toward cultured mammalian cells ( Neville et al, 2021 ). These findings were consistent with studies in which elevated doses of gallein were administered to mice or rats for up to 8 weeks with no adverse effects ( Kamal et al, 2014 ; Sanz et al, 2017 ; Karuppagounder et al, 2018 ). Likewise, bacterial long chain polyP has also recently been shown to suppress pro-inflammatory signaling cascades of the innate immune system ( Roewe et al, 2020 ).…”

Section: Discussionsupporting

confidence: 90%

Broad-Spectrum Inhibitor of Bacterial Polyphosphate Homeostasis Attenuates Virulence Factors and Helps Reveal Novel Physiology of Klebsiella pneumoniae and Acinetobacter baumannii

et al. 2021

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Acinetobacter baumannii and Klebsiella pneumoniae currently rank amongst the most antibiotic-resistant pathogens, responsible for millions of infections each year. In the wake of this crisis, anti-virulence therapeutics targeting bacterial polyphosphate (polyP) homeostasis have been lauded as an attractive alternative to traditional antibiotics. In this work, we show that the small molecule gallein, a known G-protein βγ subunit modulator, also recently proven to have dual-specificity polyphosphate kinase (PPK) inhibition in Pseudomonas aeruginosa, in turn exhibits broad-spectrum PPK inhibition in other priority pathogens. Gallein treatment successfully attenuated virulence factors of K. pneumoniae and A. baumannii including biofilm formation, surface associated motility, and offered protection against A. baumannii challenge in a Caenorhabditis elegans model of infection. This was highlighted most importantly in the critically understudied A. baumannii, where gallein treatment phenocopied a ppk1 knockout strain of a previously uncharacterized PPK1. Subsequent analysis revealed a unique instance of two functionally and phenotypically distinct PPK1 isoforms encoded by a single bacterium. Finally, gallein was administered to a defined microbial community comprising over 30 commensal species of the human gut microbiome, demonstrating the non-disruptive properties characteristic of anti-virulence treatments as microbial biodiversity was not adversely influenced. Together, these results emphasize that gallein is a promising avenue for the development of broad-spectrum anti-virulence therapeutics.

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Section: Discussionsupporting

confidence: 90%

Broad-Spectrum Inhibitor of Bacterial Polyphosphate Homeostasis Attenuates Virulence Factors and Helps Reveal Novel Physiology of Klebsiella pneumoniae and Acinetobacter baumannii

et al. 2021

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“…The underlying mechanisms of the anti-inflammatory effects of these agents differ. Gallein, through G inhibition, attenuates neutrophil chemotaxis in the paw edema mouse model (10), T and B lymphocyte activation in mouse lupus nephritis (20), and macrophage activation in myocarditis (37). Several SSRIs, including paroxetine and fluoxetine, exert anti-inflammatory effects that are not completely dependent on the serotonin system (38,39).…”

Section: Discussionmentioning

confidence: 99%

Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis

et al. 2021

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Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein–coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein–coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is unknown. Thus, in a surgical OA mouse model, we performed genetic GRK2 deletion in chondrocytes or pharmacological inhibition with the repurposed U.S. Food and Drug Administration (FDA)–approved antidepressant paroxetine. Both GRK2 deletion and inhibition prevented CH, abated OA progression, and promoted cartilage regeneration. Supporting experiments with cultured human OA cartilage confirmed the ability of paroxetine to mitigate CH and cartilage degradation. Our findings present elevated GRK2 signaling in chondrocytes as a driver of CH in OA and identify paroxetine as a disease-modifying drug for OA treatment.

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“…M1 macrophages are activated by inflammatory stimuli such as interferon (IFN) γ and secrete/trigger numerous proinflammatory cytokines and chemokines [ 9 ]. Conversely, M2 macrophages are anti-inflammatory [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects

Karuppagounder

Pinamont

Yoshioka

et al. 2022

IJMS

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The G-protein-coupled receptor kinase 2 (GRK2) is an important regulator of inflammation and pathological macrophage phenotype in a variety of diseases. We hypothesize that Gβγ-GRK2 signaling promotes the early inflammatory response and chondrocyte loss in osteoarthritis (OA). Using the destabilization of the medial meniscus (DMM) model in 12-week-old male C57BL/6 mice, we determined the role of Gβγ-GRK2 signaling in synovitis, macrophage activation, and OA development. We achieved Gβγ-GRK2 inhibition at the time of DMM by administering the Gβγ inhibitor “gallein” and the GRK2 inhibitor “paroxetine” daily, starting from 2 days before DMM surgery, for a duration of 1 or 12 weeks. Synovial and cartilage structural changes were evaluated by histomorphometry, and molecular events and macrophage activation were examined. We studied the direct role of Gβγ-GRK2 in synovitis and macrophage activation in vitro using SW982 and THP1 cells. Continuous Gβγ-GRK2 inhibition initiated at the time of DMM attenuated OA development and decreased chondrocyte loss more effectively than delayed treatment. GRK2 expression and the M1 macrophage phenotype were elevated in the inflamed synovium, while early gallein and paroxetine treatment for 1 and 12 weeks following DMM resulted in their reduction and an upregulated M2 macrophage phenotype. In vitro experiments showed that Gβγ-GRK2 inhibition attenuated synoviocyte inflammation and the M1 phenotype. We show that early Gβγ-GRK2 inhibition is of higher therapeutic efficacy in OA than delayed inhibition, as it prevents OA development by inhibiting the early inflammatory response.

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Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats

Cited by 12 publications

References 31 publications

Broad-Spectrum Inhibitor of Bacterial Polyphosphate Homeostasis Attenuates Virulence Factors and Helps Reveal Novel Physiology of Klebsiella pneumoniae and Acinetobacter baumannii

Broad-Spectrum Inhibitor of Bacterial Polyphosphate Homeostasis Attenuates Virulence Factors and Helps Reveal Novel Physiology of Klebsiella pneumoniae and Acinetobacter baumannii

Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis

Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects

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