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Recent research has revealed a bidirectional crosstalk between the aryl hydrocarbon receptor (AhR) and the Toll-like receptor 4 (TLR4), two important regulators of innate immunity and inflammation. This active, bidirectional interaction influences immune mechanisms in both health and disease. AhR, a xenobiotic-activated transcription factor, inhibits TLR4-induced inflammation by blocking NF-κB signaling, increasing IL-10 expression, and regulating macrophage and microglial polarization. TLR4 is a microbial pattern recognition receptor that enhances AhR expression, thereby promoting immune homeostasis through a feedback mechanism. Endogenous AhR ligands, like kynurenic acid, can reduce inflammation by targeting GPR35, STAT3, and α7nAChR. This review summarizes previous research on how the AhR-TLR4 axis regulates immune suppression and anti-inflammatory resolution in various tissues, through mechanisms such as epigenetic modification and IL-10/IL-22 induction. The AhR-TLR4 interaction offers potential therapeutic solutions for autoimmune diseases, chronic inflammation, and cancer, but its effects are context-dependent. Proper modulation of this pathway is crucial to avoid adverse outcomes and design targeted immunomodulatory therapies.

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Reciprocal Crosstalk Between AhR and TLR4: Molecular Mechanisms and Therapeutic Implications in Inflammation and Disease

  • 会议论文

  • 发表日期：

    2026年

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  • Maria Al-Filali,
  • Adna Ašić

摘要

Recent research has revealed a bidirectional crosstalk between the aryl hydrocarbon receptor (AhR) and the Toll-like receptor 4 (TLR4), two important regulators of innate immunity and inflammation. This active, bidirectional interaction influences immune mechanisms in both health and disease. AhR, a xenobiotic-activated transcription factor, inhibits TLR4-induced inflammation by blocking NF-κB signaling, increasing IL-10 expression, and regulating macrophage and microglial polarization. TLR4 is a microbial pattern recognition receptor that enhances AhR expression, thereby promoting immune homeostasis through a feedback mechanism. Endogenous AhR ligands, like kynurenic acid, can reduce inflammation by targeting GPR35, STAT3, and α7nAChR. This review summarizes previous research on how the AhR-TLR4 axis regulates immune suppression and anti-inflammatory resolution in various tissues, through mechanisms such as epigenetic modification and IL-10/IL-22 induction. The AhR-TLR4 interaction offers potential therapeutic solutions for autoimmune diseases, chronic inflammation, and cancer, but its effects are context-dependent. Proper modulation of this pathway is crucial to avoid adverse outcomes and design targeted immunomodulatory therapies.