Wang, Chen-YuChen-YuWangWang, Jen-YuJen-YuWangChou, Yi-YiYi-YiChouLin, Chi-ChienChi-ChienLinLin, Yu-TsunYu-TsunLinWu, Chi-ShengChi-ShengWuJR-SHIUAN LINChu, Ching-LiangChing-LiangChu2026-01-222026-01-222025-03https://scholars.lib.ntu.edu.tw/handle/123456789/735538The gut CD103 tolerogenic dendritic cells play a key role in maintaining immune balance by inducing oral tolerance, which has been implied in reducing autoimmunity. We recently reported that the oral administration of a fungal protein Lingzhi-8 (LZ-8) prevented autoimmune colitis in mice via maintaining barrier integrity. Here, we examined the functional effect of LZ-8 on gut CD103 DCs and on autoimmune psoriasis in a mouse model. After orally administered LZ-8 to mice, the numbers of CD103 DCs and their retinaldehyde dehydrogenase 2 (RALDH2) activities were increased in the mesenteric lymph nodes (mLNs), which were associated with increased regulatory T cell (Treg) in the spleen and LNs. This suggests that LZ-8 induces oral tolerance by enhancing the RALDH2 activity of CD103 DCs. In addition, the imiquimod (IMQ)-induced psoriasis-like dermatitis was attenuated in mice after LZ-8 pretreatment. In the mechanistic study, we generated gut CD103 DC-like cells from bone marrow (BM) of wild-type mouse and cultured them in the presence of retinoic acid (RA) in vitro. We found that LZ-8 directly enhanced the RALDH2 activity of these RA-primed CD103 DCs, which was dependent on Dectin-1 and Syk signaling pathways but not TLR4. Together, our study demonstrated that LZ-8 facilitated gut tolerogenic CD103 DC-mediated immunosuppression by enhancing RALDH2 activity, increasing Treg cell population, and signaling through Dectin-1 and Syk. Our findings provide a novel strategy for treating psoriasis and potentially other autoimmune diseases.enCD103(+) dendritic cellLing Zhi-8Oral tolerancePsoriasisRegulatory T cellRetinal dehydrogenase 2journal article10.1016/j.biopha.2025.11791039954596