Condition Focus: Hyperuricaemia — Pre-Crystallisation NLRP3 Activation

This study from Braga and colleagues, published in Nature’s Scientific Reports, challenged a fundamental assumption about gout: that inflammation only begins when urate crystals form. The researchers demonstrated that soluble uric acid — the dissolved form present in the blood of every hyperuricaemic patient, before any crystals appear — is itself sufficient to activate the NLRP3 inflammasome.

The mechanism is mitochondrial. Soluble urate enters macrophages and disrupts mitochondrial function, generating excessive reactive oxygen species (ROS). These mitochondrial ROS then activate the NLRP3 inflammasome through the MyD88 signalling pathway, leading to caspase-1 activation and IL-1β release. In extreme cases, this process triggers pyroptosis — a form of inflammatory cell death that releases even more danger signals into the tissue.

The clinical implication is profound: gout patients may be experiencing low-level NLRP3-driven inflammation even between flares, driven by their chronically elevated serum urate. This “subclinical inflammation” may contribute to the progressive joint damage, cardiovascular risk, and metabolic dysfunction associated with chronic hyperuricaemia — conditions that persist even when patients are not experiencing obvious flares.

For photobiomodulation, this finding is uniquely relevant because the activation pathway is mitochondrial. PBM’s primary mechanism of action — photon absorption by cytochrome c oxidase in the mitochondrial electron transport chain — directly targets the organelle generating the pathological ROS that activates NLRP3.

G.O.A.T. for Gout Alignment:
This study identifies the G.O.A.T.’s primary mechanistic target: mitochondrial ROS production. The G.O.A.T.’s 660 nm and 850 nm wavelengths are absorbed by cytochrome c oxidase, modulating mitochondrial electron transport and ROS output. This suggests potential benefit not only during acute flares but as maintenance therapy for patients with chronic hyperuricaemia — addressing the subclinical inflammatory burden between flares.

Link to original research here

Editor’s note: The mitochondrial ROS pathway demonstrated here is precisely what PBM modulates, as reviewed in Hamblin 2018. The TXNIP pathway through which mitochondrial ROS activates NLRP3 is detailed in Kim et al 2023. For the biphasic nature of PBM’s mitochondrial effects, where low doses reduce ROS in stressed cells, see Huang et al 2009. The downstream IL-1β suppression is demonstrated with dual-wavelength PBM in Shamloo et al 2023.

Related Articles

• Mitochondrial Redox Signaling and PBM: ROS Reduction in Stressed Cells – Hamblin 2018
• Mechanism of NLRP3 Inflammasome Activation in Gout – Kim et al 2023
• Biphasic Dose Response in PBM: Arndt-Schulz Curve – Huang et al 2009
• PBM Suppresses NLRP3 Inflammasome Outputs with Dual Wavelength – Shamloo et al 2023
• PBM Reduces Oxidative Stress and Inflammation in Knee OA – Yamada et al 2020

Key Takeaways

• Soluble uric acid activates NLRP3 before crystals form — via mitochondrial ROS
• Chronic hyperuricaemia may cause low-level NLRP3 inflammation even between flares
• Mechanism is mitochondrial — the exact organelle that PBM targets via cytochrome c oxidase
• Supports rationale for maintenance PBM therapy, not just acute flare treatment
• Can trigger pyroptosis (inflammatory cell death), amplifying tissue damage

Study Overview

Full Citation

Braga TT, Forni MF, Correa-Costa M, et al. (2017). Soluble uric acid activates the NLRP3 inflammasome. Scientific Reports, 7, 39884. View Publication