Short chain fatty acids: Master regulators of cutaneous immunity and potential candidates for therapeutic interventions
Final Report Abstract
The basic rationale for this project was the observation that short-chain fatty acids (SCFA) can inhibit inflammatory reactions and that this is in major parts due to the induction/activation of regulatory T cells (Treg). SCFA are bacterial fermentation products and include butyrate, propionate and acetate. For our studies we selected sodium butyrate (SB) as the major SCFA since it turned to be most potent one. SB appears to modulate antigen presenting cells in such a way that they do not induce sensitization but suppression via induction of Foxp3+ Treg. The characterization of SB as an immunosuppressor was basically performed in the murine model of hapten-induced contact hypersensitivity. To study wehter SB acts in a similar fashion in other inflammatory dermatoses we focused on psoriasis and utilized the murine psoriasis-like inflammation model induced by the immunomodulatory imiquimod (IMQ). Topical application of IMQ induced thickening of the skin, scales and inflammation. This was associated with an upregulation of interleukin (IL)-17, downregulation of IL-10 and Foxp3. Topically applied SB reduced IMQ-induced inflammation and downregulated IL-17- and induced IL-10- and Foxp3-transcripts. The mitigating effect of SB was due to Treg, since it was lost upon depletion of Treg in DEREG mice. Treg isolated from blood of psoriatic patients were reduced in their suppressive activity which was normalized by SB. The fewer Treg numbers in biopsies of psoriatic lesions as well as enhanced IL-17-, IL-6- and reduced IL-10- and Foxp3-expression levels were restored by SB. These data indicated that psoriasis is associated with an impairment of Treg and an altered cytokine milieu. SCFA appear to restore these alterations thereby harboring therapeutic potential for psoriasis. SCFA exert their anti-inflammatory effects via activation of G-protein coupled receptors (GPR), in particular GPR109a/HCA2 and GPR43. Therefore, alterations in the expression of GPR may contribute to the pathogenesis of inflammatory dermatoses. To elucidate whether this applies for psoriasis the expression of GPR in psoriatic skin was analyzed. Keratinocytes in lesional psoriatic skin expressed significantly lower levels of GPR109a and GPR43. GPR expression was also lower in non-lesional psoriatic skin in comparison to control skin, but the downregulation was much less pronounced than in lesional skin. Thus one may speculate that psoriatic keratinocytes are less susceptible to the anti-inflammatory effects of SCFA and that the down-regulation may play a role in the pathogenesis of psoriasis. Since SCFA signal via HCA2, and HCA2 expression is reduced in lesional psoriatic skin, we studied the effect of HCA2 in the IMQ model. HCA2 knock-out (HCA2-KO) mice reacted to IMQ with stronger inflammation, presumably due to an impaired function of Treg. Surprisingly, injection of Treg from HCA2-KO mice even enhanced the IMQ reaction, indicating that in the absence of HCA2 Treg switch from a suppressive into a proinflammatory type. HCA2-KO mice differed in the composition of the skin microbiome from WT mice. Co-housing reversed the exaggerated response to IMQ and prevented the alteration of Treg, indicating that the microbiome dictates the outcome of the inflammatory reaction. The switch of Treg into a proinflammatory type in HCA2-KO mice appears to be a downstream phenomenon. This opens the opportunity to reduce the inflammatory tendency by altering the skin microbiome.
Publications
- Decreased expression of G-protein-coupled receptors GPR43 and GPR109a in psoriatic skin can be restored by topical application of sodium butyrate. Arch Dermatol Res. 2018;310:751-758
Krejner A, Bruhs A, Mrowietz U, Wehkamp U, Schwarz T, Schwarz A
(See online at https://doi.org/10.1007/s00403-018-1865-1) - Induction of regulatory T cells and correction of cytokine dysbalance by short chain fatty acids – Implications for the therapy of psoriasis. J Invest Dermatol. 2021;141:95-104
Schwarz A, Philippsen R, Schwarz T
(See online at https://doi.org/10.1016/j.jid.2020.04.031)
