Pharmacological Potential of NOX2 Agonists in Inflammatory Conditions

Hultqvist, Malin; Olofsson, Peter; Wallner, Fredrik K.; Holmdahl, Rikard

doi:10.1089/ars.2013.5788

Cited by 25 publications

(20 citation statements)

References 120 publications

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“…Redox modifications of lipids and small molecule mediators might be of relevance. Could NOX2 activators be used for the treatment of mycobacterial disease? Indeed, NOX2 activators have been described, but so far their use has been rather focused on prevention and treatment of autoimmunity associated with the CGD phenotype, in particular Ncf1 mutant (Hultqvist et al ., 2006; 2014). These compounds appear well supported in animals and should be tested for mycobacterial disease. Should a prescreening for CGD performed prior to BCG vaccination?…”

Section: Resultsmentioning

confidence: 99%

Phagocyte NADPH oxidase, chronic granulomatous disease and mycobacterial infections

2014

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SummaryInfection of humans with Mycobacterium tuberculosis remains frequent and may still lead to death. After primary infection, the immune system is often able to control M. tuberculosis infection over a prolonged latency period, but a decrease in immune function (from HIV to immunosenescence) leads to active disease. Available vaccines against tuberculosis are restricted to BCG, a live vaccine with an attenuated strain of M. bovis. Immunodeficiency may not only be associated with an increased risk of tuberculosis, but also with local or disseminated BCG infection. Genetic deficiency in the reactive oxygen species (ROS)-producing phagocyte NADPH oxidase NOX2 is called chronic granulomatous disease (CGD). CGD is among the most common primary immune deficiencies. Here we review our knowledge on the importance of NOX2-derived ROS in mycobacterial infection. A literature review suggests that human CGD patient frequently have an increased susceptibility to BCG and to M. tuberculosis. In vitro studies and experiments with CGD mice are incomplete and yieldedat least in part -contradictory results. Thus, although observations in human CGD patients leave little doubt about the role of NOX2 in the control of mycobacteria, further studies will be necessary to unequivocally define and understand the role of ROS.

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Section: Resultsmentioning

confidence: 99%

Phagocyte NADPH oxidase, chronic granulomatous disease and mycobacterial infections

2014

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“…This small molecule was selected from a high-throughput screening for capacity to induce NOX2-derived ROS release in a human neutrophil-like cell line and in fresh rat phagocytes (59). Selected compounds from this screen were then validated for their ROS-inducing capacity and one lead molecule, the sulfonamide compound RE-02, was selected for treatment of PIL.…”

Section: Discussionmentioning

confidence: 99%

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps

et al. 2017

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“…A compound library containing drug-like small molecules was used in a screening study to identify novel NADPH-oxidase activators. 33 39 ) and PBP10 (antagonizes primarily FPR2;…”

Section: Re-04-001 Activates Human Neutrophilsmentioning

confidence: 99%

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2 complex

Lind

Dahlgren

Holmdahl

et al. 2020

Journal of Leukocyte Biology

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The formyl peptide receptors FPR1 and FPR2 are abundantly expressed by neutrophils, in which they regulate proinflammatory tissue recruitment of inflammatory cells, the production of reactive oxygen species (ROS), and resolution of inflammatory reactions. The unique dual functionality of the FPRs makes them attractive targets to develop FPR-based therapeutics as novel anti-inflammatory treatments. The small compound RE-04-001 has earlier been identified as an inducer of ROS in differentiated HL60 cells but the precise target and the mechanism of action of the compound was has until now not been elucidated. In this study, we reveal that RE-04-001 specifically targets and activates FPR1, and the concentrations needed to activate the neutrophil NADPH-oxidase was very low (EC 50 ∼1 nM). RE-04-001 was also found to be a neutrophil chemoattractant, but when compared to the prototype FPR1 agonist N-formyl-Met-Leu-Phe (fMLF), the concentrations required were comparably high, suggesting that signaling downstream of the RE-04-001-activated-FPR1 is functionally selective. In addition, the RE-04-001-induced response was strongly biased toward the PLC-PIP 2-Ca 2+ pathway and ERK1/2 activation but away from-arrestin recruitment. Compared to the peptide agonist fMLF, RE-04-001 is more resistant to inactivation by the MPO-H 2 O 2-halide system. In summary, this study describes RE-04-001 as a novel small molecule agonist specific for FPR1, which displays a biased signaling profile that leads to a functional selective activating of human neutrophils. RE-04-001 is, therefore, a useful tool, not only for further mechanistic studies of the regulatory role of FPR1 in inflammation in vitro and in vivo, but also for developing FPR1-specific drug therapeutics.

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Pharmacological Potential of NOX2 Agonists in Inflammatory Conditions

Cited by 25 publications

References 120 publications

Phagocyte NADPH oxidase, chronic granulomatous disease and mycobacterial infections

Phagocyte NADPH oxidase, chronic granulomatous disease and mycobacterial infections

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2 complex

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