Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs

Kaufman, Elad; Fryer, A.D.; Jacoby, David B.

doi:10.1016/j.jaci.2010.10.029

Cited by 37 publications

(50 citation statements)

References 39 publications

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“…The speed of relaxation is on the order of seconds to minutes, which is not consistent with TLR7's known transcriptional effects. TLR7-mediated relaxation of human airways did not involve a cyclooxygenase pathway, which differs from our report in guinea pig airways in vitro, in which R837 caused relaxation through both a TLR7-dependent nitric oxide pathway and TLR7-independent cyclooxygenase pathway (18). These findings represent a fundamentally unique TLR7 signaling mechanism in human airways.…”

Section: Discussioncontrasting

confidence: 94%

“…This effect is not specific to particular contractile agonists and therefore dilates airways irrespective of the mediators of bronchoconstriction. Our prior work in guinea pigs found that TLR7 relaxed airways precontracted with a variety of agonists, including histamine and potassium chloride (18). In this study, airway contractions were induced with either methacholine in vitro or by parasympathetic nerve stimulation in vivo.…”

Section: Discussionmentioning

confidence: 83%

“…Alternatively, neuronal TLR7 may cause nitric oxide production by airway smooth muscle via an intermediate cell. Although airway epithelium also expresses TLR7 (3), we have previously shown that epithelium is not necessary for TLR7's relaxant effect (18). TLR7's expression by airway nerves also suggests that airway nerves have a role in the detection and response to respiratory viruses.…”

Section: Discussionmentioning

confidence: 99%

“…This TLR7-independent effect in human airways is novel. In guinea pigs, PolyU exclusively activated TLR7 (18). In humans, however, uridylic acid and adenylic acid-rich motifs Figure 5.…”

Section: Discussionmentioning

confidence: 99%

“…Although TLR7 activation classically triggers transcription of antiviral interferons and proinflammatory cytokines via nuclear factor-kB (8), we recently found a novel TLR7 pathway that causes rapid bronchodilation in guinea pigs (18). This effect was distinct from TLR7's known transcriptional pathways.…”

mentioning

confidence: 97%

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Toll-like Receptor 7 Rapidly Relaxes Human Airways

Drake

Scott

Proskocil

et al. 2013

Am J Respir Crit Care Med

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Rationale: Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs. Objectives: To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs. Methods: Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs. Measurements and Main Results: The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways. Conclusions: TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.Keywords: Toll-like receptor 7; imiquimod; nitric oxide; asthma; nerve Toll-like receptor (TLR) 7 is a pattern recognition receptor in the lungs (1-3) that detects single-stranded RNA genomes, common to many respiratory viruses (4). Respiratory viruses cause airway hyperreactivity (an abnormal tendency to contract) (5, 6) and asthma exacerbations (7). A role for TLR7 in the development of virus-induced airway hyperreactivity has been proposed, because TLR7 activation causes a proinflammatory type 1 T-helper cell (Th1) immune response (8) and because TLR7 polymorphisms have been associated with asthma (9). In patients with asthma, however, TLR7 responses were reduced (10). Furthermore, in mouse models of allergic airway inflammation, the TLR7 imidazoquinoline agonists imiquimod (R837) and resiquimod (R848) reduced airway hyperreactivity, airway eosinophilia, goblet cell hyperplasia, and smooth muscle hypertrophy (11-14), whereas TLR7 knockout mice were prone to the development of asthma-like airway pathology after pneumovirus infection (15). These studies suggest that TLR7 may be protective against the development of allergic type 2 T-helper cell airway inflammation, possibly by altering the Th1 versus Th2 immune balance (16). Similarly, a TLR7 agonist is currently i...

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Section: Discussioncontrasting

confidence: 94%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

“…This TLR7-independent effect in human airways is novel. In guinea pigs, PolyU exclusively activated TLR7 (18). In humans, however, uridylic acid and adenylic acid-rich motifs Figure 5.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

See 3 more Smart Citations

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Drake

Scott

Proskocil

et al. 2013

Am J Respir Crit Care Med

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TLR Activation and Allergic Disease: Early Life Microbiome and Treatment

Michels

Lukacs

Fonseca

2018

Curr Allergy Asthma Rep

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Emerging role of Toll-like receptors in the control of pain and itch

2012

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Toll-like receptors (TLRs) are germline-encoded pattern-recognition receptors (PRRs) to initiate innate immune responses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns (PAMPs). After tissue injury or cellular stress, TLRs can also detect endogenous ligands known as danger-associated molecular patterns (DAMPs). TLRs are expressed in various cell types in the central nervous system (CNS), including non-neuronal and neuronal cells, and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs (such as TLR2, 3, and 4) induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neuropathic pain. In particular, primary sensory neurons, such as nociceptors express TLRs (e.g., TLR4 and TLR7) to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of the affected people, insights into TLR signaling in nervous system will open a new avenue for the management of clinical pain and itch.

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Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs

Cited by 37 publications

References 39 publications

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Toll-like Receptor 7 Rapidly Relaxes Human Airways

TLR Activation and Allergic Disease: Early Life Microbiome and Treatment

Emerging role of Toll-like receptors in the control of pain and itch

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