The fungal protein Lingzhi-8 ameliorates psoriasis-like dermatitis in mice through gut CD103⁺ tolerogenic dendritic cells, retinaldehyde dehydrogenase 2, and Dectin-1

The 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.