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Published on: June 8, 2022
Unique Polypharmacology Nuclear Receptor Modulator Blocks Inflammatory Signaling Pathways
Mi Ra Chang1, Anthony Ciesla1, Timothy S Strutzenberg1
1Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States.
Abstract:
Obesity and rheumatic disease are mechanistically linked via chronic inflammation. The orphan receptor TREM-1 (triggering receptor expressed on myeloid cells-1) is a potent amplifier of proinflammatory and noninfectious immune responses. Here, we show that the pan modulator SR1903 effectively blocks TREM-1 activation. SR1903 emerged from a chemical series of potent RORγ inverse agonists, although unlike close structural analogues, it has modest agonist activity on LXR and weak repressive activity (inverse agonism) of PPARγ, three receptors that play essential roles in inflammation and metabolism. The anti-inflammatory and antidiabetic efficacy of this unique modulator in collagen-induced arthritis and diet-induced obesity mouse models is demonstrated. Interestingly, in the context of obesity, SR1903 aided in the maintenance of the thymic homeostasis unlike selective RORγ inverse agonists. SR1903 was well-tolerated following chronic administration, and combined, these data suggest that it may represent a viable strategy for treatment of both metabolic and inflammatory disease. More importantly, the ability of SR1903 to block LPS signaling suggests the potential utility of this unique polypharmacological modulator for treatment of innate immune response disorders.
Insights
A novel compound, SR1903, effectively blocks TREM-1 activation, offering a potential treatment for both metabolic and inflammatory diseases like obesity and rheumatic conditions.
Area of Science:
- Immunology
- Metabolic disease research
- Pharmacology
Background:
- Obesity and rheumatic diseases share underlying chronic inflammation.
- TREM-1 (triggering receptor expressed on myeloid cells-1) amplifies inflammatory responses.
- Existing treatments often target single pathways, necessitating broader approaches.
Purpose of the Study:
- To investigate the efficacy of SR1903, a pan modulator, in preclinical models of inflammation and metabolic dysfunction.
- To characterize the polypharmacological profile of SR1903, including its activity on RORγ, LXR, and PPARγ.
- To evaluate the therapeutic potential of SR1903 for treating interconnected inflammatory and metabolic disorders.
Main Methods:
- Utilized collagen-induced arthritis and diet-induced obesity mouse models.
- Assessed the impact of SR1903 on TREM-1 activation and inflammatory markers.
- Evaluated SR1903's effects on thymic homeostasis and LPS signaling.
- Characterized SR1903's activity across RORγ, LXR, and PPARγ receptors.
Main Results:
- SR1903 demonstrated significant anti-inflammatory and anti-diabetic effects in mouse models.
- The compound effectively blocked TREM-1 activation and LPS signaling.
- SR1903 maintained thymic homeostasis in obese mice, unlike selective RORγ inverse agonists.
- SR1903 was well-tolerated upon chronic administration.
Conclusions:
- SR1903 is a unique polypharmacological modulator with potential for treating linked metabolic and inflammatory diseases.
- Blocking TREM-1 and modulating RORγ, LXR, and PPARγ offers a promising therapeutic strategy.
- SR1903's ability to impact innate immune responses warrants further investigation for related disorders.
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