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TnP and AHR-CYP1A1 Signaling Crosstalk in an Injury-Induced Zebrafish Inflammation Model
Geonildo Rodrigo Disner1,2, Thales Alves de Melo Fernandes3, Milton Yutaka Nishiyama-Jr3
1Immunoregulation Unit, Laboratory of Applied Toxinology (CeTICS/FAPESP), Butantan Institute, São Paulo 05585-000, Brazil.
Pharmaceuticals (Basel, Switzerland)
|September 28, 2024
Summary
Thalassophryne nattereri Peptide (TnP) modulates Aryl Hydrocarbon Receptor (AHR) signaling, acting as a CYP1A inhibitor. This interaction influences inflammatory responses and offers potential for novel therapeutic strategies.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Aryl Hydrocarbon Receptor (AHR) signaling regulates xenobiotic metabolism, inflammation, and immunity.
- Thalassophryne nattereri Peptide (TnP) from toadfish venom shows anti-inflammatory and immunomodulatory effects.
- The interaction between TnP and AHR signaling is currently unexplored.
Purpose of the Study:
- To investigate the molecular mechanisms of TnP on the AHR-cytochrome P450, family 1 (CYP1) pathway.
- To analyze the effects of TnP on injury-induced inflammation in zebrafish larvae using transcriptomic analysis.
- To elucidate the role of AHR2 in mediating TnP's effects.
Main Methods:
- Transcriptomic analysis of wild-type and Ahr2-knockdown zebrafish larvae under inflammation.
- Use of Cyp1a reporters to monitor AHR pathway activation.
- In vitro studies to confirm TnP's inhibitory activity on CYP1A.
Main Results:
- TnP did not directly activate AHR but potentiated FICZ-induced AHR activation, suggesting CYP1A inhibition.
- Inflammation induced significant transcriptomic changes, with most differentially expressed genes (DEGs) upregulated.
- Ahr2 knockdown and higher TnP doses increased DEG numbers; TnP specifically induced Hspa5, Hsp90aa1.2, Cxcr3.3, and Mpeg1.2 expression.
Conclusions:
- TnP modulates the AHR-CYP1 complex, potentially acting as a CYP1A inhibitor.
- TnP influences inflammatory and oxidative stress pathways, partly through AHR-dependent mechanisms.
- These findings suggest potential therapeutic strategies leveraging natural compounds and AHR modulation for inflammatory conditions.
