Analysis reveals how the dietary flavonoid promotes regulatory T cell improvement and suppresses irritation by means of key immune pathways.
Examine: Kaempferol Exerts Anti-Inflammatory Results by Accelerating Treg Improvement through Aryl Hydrocarbon Receptor-Mediated and PU.1/IRF4-Dependent Transactivation of the Aldh1a2/Raldh2 Gene in Dendritic Cells. Picture Credit score: Danijela Maksimovic/Shutterstock.com
In a latest article revealed within the Allergy, a gaggle of researchers studied how kaempferol, a dietary flavonoid, promotes regulatory T cell (Treg) improvement by activating the Aldh1a2/Raldh2 gene in dendritic cells by means of the aryl hydrocarbon receptor (AhR) and PU.1/IRF4 pathways.
Background
Raldh2, encoded by the Aldh1a2 gene, is expressed in intestinal dendritic cells (DCs) and performs a essential function in immune regulation. It converts retinal into retinoic acid (RA), a key ligand for the nuclear receptor retinoic acid receptor (RAR). RA drives the event of Tregs by activating Forkhead field P3 (Foxp3), the grasp transcription issue for Treg differentiation.
Tregs are important for sustaining immune tolerance and stopping inflammatory ailments. Nonetheless, the regulatory mechanisms of Aldh1a2 expression and Raldh2 operate stay unclear, necessitating additional analysis to uncover pathways that improve Treg improvement and immune homeostasis.
The examine
The examine started by screening dietary compounds for his or her skill to advertise Treg improvement by means of Aldh1a2 activation in DCs. Kaempferol was recognized as the simplest compound in growing Aldh1a2 messenger Ribonucleic acid (mRNA) expression.
Experiments utilizing bone marrow-derived dendritic cells (BMDCs) and migratory DCs (migDCs) from mesenteric lymph nodes (MLNs) confirmed that kaempferol therapy enhanced Raldh2 enzymatic exercise.
To guage the practical impression of kaempferol-induced Raldh2 exercise, DCs pretreated with kaempferol have been co-cultured with naïve Cluster of Differentiation (CD)4+ T cells.
The outcomes confirmed a major enhance within the frequency of Foxp3+ Tregs, demonstrating that kaempferol confers Treg-inducing potential to DCs. This impact was accompanied by suppression of T-cell proliferation, additional indicating kaempferol’s function in selling immune tolerance.
The examine subsequent investigated the molecular mechanisms behind kaempferol-induced Aldh1a2 expression. The aryl hydrocarbon receptor (AhR), a transcription issue and identified goal of kaempferol, was recognized as a key mediator. Kaempferol therapy elevated each the mRNA and protein ranges of AhR in BMDCs.
Knockdown of AhR utilizing small interfering (si)RNA abolished the kaempferol-induced enhance in Aldh1a2 mRNA and Raldh2 exercise, confirming the dependence of this pathway on AhR. In distinction, therapy with 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, lowered Aldh1a2 expression, whereas an AhR antagonist, CH-223191, enhanced it.
These outcomes recommend that kaempferol features by antagonizing AhR, thereby relieving its inhibitory impact on Aldh1a2 expression.
The transcription components PU.1 and IRF4 are identified to transactivate Aldh1a2 by binding to its upstream enhancer areas in DCs. The examine examined the function of those components in kaempferol-induced Aldh1a2 expression.
Kaempferol therapy elevated each PU.1 and IRF4 mRNA and protein ranges in BMDCs. Chromatin immunoprecipitation (ChIP) assays additional demonstrated that kaempferol enhanced PU.1 recruitment to the Aldh1a2 enhancer. Knockdown of Spi1 (PU.1-encoding gene) or Irf4 utilizing siRNA abolished kaempferol-induced Aldh1a2 expression, confirming the requirement of those components.
Apparently, the examine revealed that AhR negatively regulates PU.1 post-transcriptionally whereas additionally repressing IRF4 transcription. Kaempferol antagonizes AhR to alleviate this repression, resulting in elevated PU.1 and IRF4 expression and subsequent Aldh1a2 activation. These findings spotlight a posh regulatory interaction involving AhR, PU.1, and IRF4.
The examine prolonged its findings to an in vivo mouse mannequin. Intraperitoneal administration of an AhR antagonist in mice elevated the frequency of DCs with Raldh2 exercise within the mesenteric lymph nodes.
Moreover, administration of kaempferol-treated BMDCs into mice enhanced the frequency of Foxp3+ Tregs in Peyer’s patches, demonstrating the physiological relevance of kaempferol’s results on DCs.
To guage kaempferol’s function in allergic irritation, the examine employed an ovalbumin (OVA)-induced meals allergy mannequin in mice. Kaempferol therapy throughout the sensitization part considerably suppressed allergic diarrhea and lowered the fast drop in physique temperature noticed after the OVA problem.
These outcomes recommend that kaempferol enhances immune tolerance by selling Treg improvement and suppressing allergic responses.
Conclusions
To summarize, the examine concludes that kaempferol enhances Treg improvement by upregulating Aldh1a2 expression and Raldh2 exercise in DCs.
This impact is mediated by means of the antagonism of the AhR, which relieves its repression of the transcription components PU.1 and IRF4.
The findings exhibit that kaempferol confers Treg-inducing potential to DCs, selling immune tolerance and suppressing allergic irritation in vivo.
