A recent study published in Allergy has highlighted the potential of kaempferol, a dietary flavonoid, to boost immune tolerance and combat allergic responses. Researchers discovered that kaempferol promotes the development of regulatory T cells (Tregs) by activating key genes in dendritic cells (DCs), paving the way for better management of immune-related conditions.
Raldh2, an enzyme encoded by the Aldh1a2 gene, plays a pivotal role in immune regulation. It is expressed in intestinal dendritic cells (DCs) and facilitates the conversion of retinal into retinoic acid (RA), which in turn activates the retinoic acid receptor (RAR). RA is known to drive Treg development by activating Foxp3, the master transcription factor responsible for Treg differentiation. Tregs are crucial for maintaining immune tolerance and preventing inflammatory diseases. However, the regulatory mechanisms governing Aldh1a2 expression and Raldh2 function remain unclear, necessitating further research to identify pathways that can enhance Treg development and immune stability.
The research team began by screening various dietary compounds to determine their ability to promote Treg development through the activation of Aldh1a2 in DCs. Among the compounds tested, kaempferol emerged as the most effective at boosting Aldh1a2 messenger RNA (mRNA) expression.
Experiments using bone marrow-derived dendritic cells (BMDCs) and migratory DCs (migDCs) from mesenteric lymph nodes (MLNs) revealed that kaempferol treatment significantly increased Raldh2 enzymatic activity. To assess the functional impact of kaempferol-induced Raldh2 activity, DCs treated with kaempferol were co-cultured with naïve CD4+ T cells. The results showed a notable increase in the frequency of Foxp3+ Tregs, indicating that kaempferol confers Treg-inducing potential to DCs. This effect was accompanied by suppression of T-cell proliferation, further confirming kaempferol’s role in promoting immune tolerance.
The study then delved into the molecular mechanisms underlying kaempferol-induced Aldh1a2 expression. Researchers identified the aryl hydrocarbon receptor (AhR), a transcription factor known to be targeted by kaempferol, as a key mediator. Kaempferol treatment led to increased mRNA and protein levels of AhR in BMDCs. When AhR was knocked down using small interfering RNA (siRNA), the kaempferol-induced increase in Aldh1a2 mRNA and Raldh2 activity was abolished, confirming the dependence of this pathway on AhR. In contrast, treatment with 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, reduced Aldh1a2 expression, while an AhR antagonist, CH-223191, enhanced it.
These findings suggest that kaempferol functions by antagonizing AhR, thereby relieving its inhibitory effect on Aldh1a2 expression.
Additionally, the transcription factors PU.1 and IRF4 were identified as important players in kaempferol-induced Aldh1a2 expression. These factors transactivate Aldh1a2 by binding to its upstream enhancer regions in DCs. Kaempferol treatment increased both PU.1 and IRF4 mRNA and protein levels in BMDCs, and chromatin immunoprecipitation (ChIP) assays confirmed that kaempferol enhanced PU.1 recruitment to the Aldh1a2 enhancer. Knockdown of the PU.1-encoding gene Spi1 or Irf4 using siRNA abolished kaempferol-induced Aldh1a2 expression, confirming the necessity of these factors.
Notably, the study also found that AhR negatively regulates PU.1 post-transcriptionally and represses IRF4 transcription. Kaempferol’s antagonism of AhR relieves this repression, leading to increased PU.1 and IRF4 expression, which subsequently activates Aldh1a2. These findings highlight a complex regulatory interaction between AhR, PU.1, and IRF4.
The research extended its findings to an in vivo mouse model. Intraperitoneal administration of an AhR antagonist in mice led to an increase in the frequency of DCs with Raldh2 activity in the mesenteric lymph nodes. Moreover, the administration of kaempferol-treated BMDCs into mice enhanced the frequency of Foxp3+ Tregs in Peyer’s patches, demonstrating the physiological relevance of kaempferol’s effects on DCs.
To assess kaempferol’s potential in allergic inflammation, the team used an ovalbumin (OVA)-induced food allergy model in mice. Kaempferol treatment during the sensitization phase significantly reduced allergic diarrhea and minimized the rapid drop in body temperature observed after the OVA challenge. These results suggest that kaempferol enhances immune tolerance by promoting Treg development and suppressing allergic responses.
In conclusion, this study reveals that kaempferol enhances Treg development by upregulating Aldh1a2 expression and Raldh2 activity in DCs. The mechanism behind this effect involves kaempferol’s antagonism of AhR, which relieves the repression of key transcription factors PU.1 and IRF4, ultimately leading to improved immune tolerance and reduced allergic inflammation. These findings position kaempferol as a promising dietary compound for enhancing immune function and mitigating allergic diseases.
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