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• W3035563103 abstract "Commensal microbes modulate the immune system in the colon through short-chain fatty acids, which induce regulatory T cells (Treg). Accordingly, the short-chain fatty acid sodium butyrate (SB) suppressed allergic contact dermatitis in mice through the activation of Treg. There is evidence that Treg exert the capacity to control inflammation in psoriasis. Thus, we were interested in studying the effect of SB in psoriasis, utilizing the imiquimod-induced psoriasis-like skin inflammation model. Topical application of imiquimod induced thickening of the skin, scales, and inflammation. This was associated with an upregulation of IL-17 and downregulation of IL-10 and FOXP3. Topically applied SB reduced imiquimod-induced inflammation and downregulated IL-17 and induced IL-10 and FOXP3 transcripts. The mitigating effect of SB was due to Treg because it was lost upon depletion of Treg in the depletion of regulatory T cell mice. Treg isolated from the blood of patients with psoriasis were reduced in their suppressive activity, which was normalized by SB. The fewer Treg numbers in the biopsies of psoriatic lesions as well as enhanced IL-17– and IL-6–expression levels and reduced IL-10– and FOXP3–expression levels were restored by SB. These data indicate that psoriasis is associated with an impairment of Treg and an altered cytokine milieu. Short-chain fatty acids appear to restore these alterations, thereby harboring a therapeutic potential for psoriasis. Commensal microbes modulate the immune system in the colon through short-chain fatty acids, which induce regulatory T cells (Treg). Accordingly, the short-chain fatty acid sodium butyrate (SB) suppressed allergic contact dermatitis in mice through the activation of Treg. There is evidence that Treg exert the capacity to control inflammation in psoriasis. Thus, we were interested in studying the effect of SB in psoriasis, utilizing the imiquimod-induced psoriasis-like skin inflammation model. Topical application of imiquimod induced thickening of the skin, scales, and inflammation. This was associated with an upregulation of IL-17 and downregulation of IL-10 and FOXP3. Topically applied SB reduced imiquimod-induced inflammation and downregulated IL-17 and induced IL-10 and FOXP3 transcripts. The mitigating effect of SB was due to Treg because it was lost upon depletion of Treg in the depletion of regulatory T cell mice. Treg isolated from the blood of patients with psoriasis were reduced in their suppressive activity, which was normalized by SB. The fewer Treg numbers in the biopsies of psoriatic lesions as well as enhanced IL-17– and IL-6–expression levels and reduced IL-10– and FOXP3–expression levels were restored by SB. These data indicate that psoriasis is associated with an impairment of Treg and an altered cytokine milieu. Short-chain fatty acids appear to restore these alterations, thereby harboring a therapeutic potential for psoriasis. The intestinal microbiome is known to modulate inflammatory reactions. This is achieved through the expansion and activation of regulatory T cells (Treg) (Arpaia et al., 2013Arpaia N. Campbell C. Fan X. Dikiy S. van der Veeken J. deRoos P. et al.Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.Nature. 2013; 504: 451-455Crossref PubMed Scopus (2619) Google Scholar, Furusawa et al., 2013Furusawa Y. Obata Y. Fukuda S. Endo T.A. Nakato G. Takahashi D. et al.Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.Nature. 2013; 504 ([published correction appears in Nature 2014;506:254]): 446-450Crossref PubMed Scopus (3031) Google Scholar, Nagano et al., 2012Nagano Y. Itoh K. Honda K. The induction of Treg cells by gut-indigenous Clostridium.Curr Opin Immunol. 2012; 24: 392-397Crossref PubMed Scopus (98) Google Scholar, Trompette et al., 2014Trompette A. Gollwitzer E.S. Yadava K. Sichelstiel A.K. Sprenger N. Ngom-Bru C. et al.Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis.Nat Med. 2014; 20: 159-166Crossref PubMed Scopus (1664) Google Scholar). The regulatory effects of commensal gut bacteria are not only confined to colitis but also influence inflammatory reactions of other organs like the central nervous and the airway systems (Ochoa-Repáraz et al., 2009Ochoa-Repáraz J. Mielcarz D.W. Ditrio L.E. Burroughs A.R. Foureau D.M. Haque-Begum S. et al.Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis.J Immunol. 2009; 183: 6041-6050Crossref PubMed Scopus (424) Google Scholar; Trompette et al., 2014Trompette A. Gollwitzer E.S. Yadava K. Sichelstiel A.K. Sprenger N. Ngom-Bru C. et al.Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis.Nat Med. 2014; 20: 159-166Crossref PubMed Scopus (1664) Google Scholar). It was discovered that the intestinal microbiome utilizes short-chain fatty acids (SCFA) to exert these effects. SCFA, microbiota-derived bacterial fermentation products including butyrate, propionate, and acetate, were found to modulate Treg homeostasis in the gut (Maslowski et al., 2009Maslowski K.M. Vieira A.T. Ng A. Kranich J. Sierro F. Yu D. et al.Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43.Nature. 2009; 461: 1282-1286Crossref PubMed Scopus (2161) Google Scholar, Smith et al., 2013Smith P.M. Howitt M.R. Panikov N. Michaud M. Gallii C.A. Bohlooly-Y M. et al.The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.Science. 2013; 341: 569-573Crossref PubMed Scopus (3089) Google Scholar). Accordingly, oral administration of SCFA obtained from the stool of healthy volunteers increased the number of Foxp3+ Treg in the gut of mice (Atarashi et al., 2013Atarashi K. Tanoue T. Oshima K. Suda W. Nagano Y. Nishikawa H. et al.Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota.Nature. 2013; 500: 232-236Crossref PubMed Scopus (1892) Google Scholar). However, commensals regulate inflammation not only in the gut but also in the respiratory and urogenital tract, the oral cavity, and the skin (Belkaid and Naik, 2013Belkaid Y. Naik S. Compartmentalized and systemic control of tissue immunity by commensals.Nat Immunol. 2013; 14: 646-653Crossref PubMed Scopus (244) Google Scholar). Because skin commensals also produce SCFAs (Christensen and Brüggemann, 2014Christensen G.J. Brüggemann H. Bacterial skin commensals and their role as host guardians.Benef Microbes. 2014; 5: 201-215Crossref PubMed Scopus (184) Google Scholar), we postulated that SCFA might also exert a similar regulatory function in the skin. We surmised that SCFA produced by commensal skin bacteria may also stimulate Treg in the skin. According to this line, sodium butyrate (SB) applied topically suppressed allergic contact dermatitis in mice (Schwarz et al., 2017Schwarz A. Bruhs A. Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system.J Invest Dermatol. 2017; 137: 855-864Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). This effect was associated with the induction and/or activation of Treg. Psoriasis is a chronic inflammatory dermatosis with complex pathogenesis. Several pathways appear to be involved and contribute to the broad clinical appearance (Rendon and Schäkel, 2019Rendon A. Schäkel K. Psoriasis pathogenesis and treatment.Int J Mol Sci. 2019; 20: 1475Crossref PubMed Scopus (572) Google Scholar). Psoriasis is regarded as a kind of autoimmune dermatosis (Prinz, 2017Prinz J.C. Autoimmune aspects of psoriasis: heritability and autoantigens.Autoimmun Rev. 2017; 16: 970-979Crossref PubMed Scopus (39) Google Scholar); several potential autoantigens were identified including ADAMTS-like protein 5 (Arakawa et al., 2015Arakawa A. Siewert K. Stöhr J. Besgen P. Kim S.M. Rühl G. et al.Melanocyte antigen triggers autoimmunity in human psoriasis.J Exp Med. 2015; 212: 2203-2212Crossref PubMed Scopus (221) Google Scholar) or LL-37 (Lande et al., 2014Lande R. Botti E. Jandus C. Dojcinovic D. Fanelli G. Conrad C. et al.The antimicrobial peptide LL37 is a T-cell autoantigen in Psoriasis.Nat Commun. 2014; 5 ([published correction appears in Nat Commun 2015;6:6595]): 5621Crossref PubMed Scopus (337) Google Scholar). There is clinical and experimental evidence that Treg in psoriasis are reduced in number and impaired in their activity and thus, lose their capacity to control the inflammatory response (Owczarczyk-Saczonek et al., 2018Owczarczyk-Saczonek A. Czerwińska J. Placek W. The role of regulatory T cells and antiinflammatory cytokines in psoriasis.Acta Dermatovenerol Alp Pannonica Adriat. 2018; 27: 17-23PubMed Google Scholar, Stockenhuber et al., 2018Stockenhuber K. Hegazy A.N. West N.R. Ilott N.E. Stockenhuber A. Bullers S.J. et al.Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I-driven CD8+ T cell response.J Exp Med. 2018; 215: 1987-1998Crossref PubMed Scopus (35) Google Scholar). In contrast, other studies found FOXP3+ Treg rather increased in the skin and blood of patients with psoriasis (Zhang et al., 2010Zhang L. Yang X.Q. Cheng J. Hui R.S. Gao T.W. Increased Th17 cells are accompanied by FoxP3(+) Treg cell accumulation and correlated with psoriasis disease severity.Clin Immunol. 2010; 135: 108-117Crossref PubMed Scopus (157) Google Scholar) and imiquimod (IMQ)-treated mice (Hartwig et al., 2018Hartwig T. Zwicky P. Schreiner B. Yawalkar N. Cheng P. Navarini A. et al.Regulatory T cells restrain pathogenic T helper cells during skin inflammation.Cell Rep. 2018; 25: 3564-3572Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). The increase of Treg upon IMQ administration appears to have a mitigating effect on the inflammatory response because this was exaggerated upon depletion of Treg (Hartwig et al., 2018Hartwig T. Zwicky P. Schreiner B. Yawalkar N. Cheng P. Navarini A. et al.Regulatory T cells restrain pathogenic T helper cells during skin inflammation.Cell Rep. 2018; 25: 3564-3572Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). However, it has not been elucidated yet whether activation of Treg can reduce psoriatic inflammation. Hence, we studied whether the reduced activity of Treg can be restored by the administration of SCFA. To address this issue, we utilized IMQ-induced inflammation, a murine model of psoriasis-like skin inflammation (van der Fits et al., 2009van der Fits L. Mourits S. Voerman J.S.A. Kant M. Boon L. Laman J.D. et al.Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.J Immunol. 2009; 182: 5836-5845Crossref PubMed Scopus (1363) Google Scholar), and samples from patients with psoriasis. Mice were treated with IMQ cream and received a daily dose of 62.5 mg on the shaved backs and ears for 10 days. One group of the IMQ-treated mice received SB topically on the back skin and ears for 3 days. IMQ-treated mice developed thickening of the skin, erythema, and scales. The inflammatory response was reduced upon administration of SB, whereas the vehicle had no effect (Figure 1a). This was also confirmed by measuring the ear and back skin thickness (Figure 1b). Administration of SB on normal control mice did not have an effect (Supplementary Figure S1). Biopsies were taken, and paraffin sections stained with H&E. IMQ treatment induced acanthosis, hyperkeratosis, and an inflammatory infiltrate. These changes were almost completely reversed by SB but not by the vehicle (Figure 1c). Because IMQ, though only topically applied, appears to induce also systemic immunologic alterations (van der Fits et al., 2009van der Fits L. Mourits S. Voerman J.S.A. Kant M. Boon L. Laman J.D. et al.Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.J Immunol. 2009; 182: 5836-5845Crossref PubMed Scopus (1363) Google Scholar), mice were killed 14 days after initiation of IMQ treatment and spleens obtained. As described previously, the spleens of IMQ-treated animals were remarkably enlarged. Splenomegaly was much less pronounced upon the topical application of SB (Figure 1d). Total RNA was isolated from the back skin and ears and RT-PCR for the transcription of Il-17 performed. Il-17 transcripts were significantly upregulated by IMQ (Figure 2a), which is in accordance with previous observations (van der Fits et al., 2009van der Fits L. Mourits S. Voerman J.S.A. Kant M. Boon L. Laman J.D. et al.Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.J Immunol. 2009; 182: 5836-5845Crossref PubMed Scopus (1363) Google Scholar). SB downregulated Il-17 transcripts. In turn, transcription of Il-10 was remarkably induced by SB as observed in contact hypersensitivity (Schwarz et al., 2017Schwarz A. Bruhs A. Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system.J Invest Dermatol. 2017; 137: 855-864Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). We surmise Treg as the primary source of Il-10, which was supported by the upregulation of the mRNA of the Treg-specific transcription factor Foxp3. These data support the assumption that SB might activate cutaneous Treg and thereby contribute to the downregulation of the inflammatory response. To get an idea about the cause of the splenomegaly and to identify whether Treg are the primary sources of IL-10 and IL-17, cells were obtained from the spleens and lymph nodes and subjected to FACS analysis. Cells were gated for CD25 and double-positive cells for FOXP3 and IL-10 and FOXP3 and IL-17, respectively, were analyzed. The number of FOXP3– and IL-17–expressing cells was enhanced in IMQ-treated mice, implying that the splenomegaly might be due in part to the infiltration and/or expansion of IL-17–expressing lymphocytes. This effect was prevented by SB. In addition, fewer cells expressing FOXP3 and IL-10 were detected after IMQ administration, suggesting the downregulation of IL-10 producing FOXP3+ Treg. This was also almost completely reversed by SB (Figure 2b). To determine whether SB-induced and/or -activated Tregs express CD69, CD73, and FR4, CD25-gated cells were double-stained with FOXP3 for those markers (Figure 2c). CD69, which regulates the differentiation of Treg as well as the secretion of IFN-γ, IL-17, and IL-22 (Cibrián and Sánchez-Madrid, 2017Cibrián D. Sánchez-Madrid F. CD69: from activation marker to metabolic gatekeeper.Eur J Immunol. 2017; 47: 946-953Crossref PubMed Scopus (337) Google Scholar), was upregulated by SB. A similar induction was observed on FOXP3+ cells for CD73, an ecto-5′-nucleosidase that contributes to the inhibitory function of Treg by generating adenosine (Ring et al., 2011Ring S. Enk A.H. Mahnke K. Regulatory T cells from IL-10-deficient mice fail to suppress Contact hypersensitivity reactions due to lack of adenosine production.J Invest Dermatol. 2011; 131: 1494-1502Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar), and for FR4, which is required for the activity of Treg (Kinoshita et al., 2012Kinoshita M. Kayama H. Kusu T. Yamaguchi T. Kunisawa J. Kiyono H. et al.Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon.J Immunol. 2012; 189: 2869-2878Crossref PubMed Scopus (98) Google Scholar). To prove whether the effect of SB is mediated through Treg, we utilized the depletion of regulatory T cell mice, which express a diphtheria toxin (DT) receptor-enhanced GFP under the control of the Foxp3 gene (Lahl et al., 2007Lahl K. Loddenkemper C. Drouin C. Freyer J. Arnason J. Eberl G. et al.Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease.J Exp Med. 2007; 204: 57-63Crossref PubMed Scopus (727) Google Scholar). Thus, injection of DT resulted in the selective depletion of Foxp3+ cells, which included Treg. Depletion of regulatory T cell mice were treated with IMQ for 10 days and SB for 3 days. Two groups received 1 μg DT on 3 consecutive days before IMQ treatment and on day 10. IMQ-treated mice developed thickening of the skin, erythema, and scales (Figure 3a). The depletion of Treg with DT enhanced the inflammatory response. This is in accordance with recently published findings that Foxp3+ Treg control inflammation severity in the IMQ model (Hartwig et al., 2018Hartwig T. Zwicky P. Schreiner B. Yawalkar N. Cheng P. Navarini A. et al.Regulatory T cells restrain pathogenic T helper cells during skin inflammation.Cell Rep. 2018; 25: 3564-3572Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, Stockenhuber et al., 2018Stockenhuber K. Hegazy A.N. West N.R. Ilott N.E. Stockenhuber A. Bullers S.J. et al.Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I-driven CD8+ T cell response.J Exp Med. 2018; 215: 1987-1998Crossref PubMed Scopus (35) Google Scholar). SB downregulated IMQ-induced inflammation, but this effect disappeared upon the injection of DT, implying that the anti-inflammatory effect of SB is critically dependent on Treg. These observations were confirmed by measuring the ear swelling and skin thickness (Figure 3b). Histologic analysis of biopsies confirmed these results (Figure 3c). IMQ-induced acanthosis, hyperkeratosis, and inflammation were reduced by SB, but this effect was lost upon the depletion of Treg. The systemic alterations were influenced in an identical fashion. IMQ-induced splenomegaly was reduced by SB but only in the presence of Treg (Figure 3d). To clarify whether similar observations can be made in the human system, Treg (CD4+CD25+) were isolated from the human PBMC of patients with psoriasis and healthy controls, and an in vitro suppression assay was performed. Treg isolated from the PBMC obtained from patients with psoriasis revealed reduced suppressive activity when compared with Treg obtained from healthy controls, which is in accordance with previous observations (Sugiyama et al., 2005Sugiyama H. Gyulai R. Toichi E. Garaczi E. Shimada S. Stevens S.R. et al.Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation.J Immunol. 2005; 174: 164-173Crossref PubMed Scopus (490) Google Scholar). Treatment of psoriatic and normal Treg with SB resulted in a moderate enhancement of their activity (Figure 4a), suggesting that SB exerts the capacity to restore the reduced suppressive activity of the Treg obtained from patients with psoriasis at least partially. The expression of FOXP3 on the Treg obtained from patients with psoriasis was lower than that on the Treg obtained from healthy controls, as demonstrated by FACS analysis (Figure 4b); stimulation with SB enhanced the expression of FOXP3. To evaluate the expression of FOXP3 in the skin, qRT-PCR was performed. Biopsies were taken from controls, lesional, and nonlesional psoriatic skin and placed into a 24-well plate. After, the dissection half of each biopsy was treated topically with SB or vehicle. The expression of FOXP3 was reduced in lesional skin in comparison with that of the healthy controls but upregulated upon treatment with SB. The expression of FOXP3 in the nonlesional skin was also downregulated in comparison with that of the controls but not as pronounced as in lesional psoriatic skin. Upon stimulation with SB, the expression of FOXP3 in nonlesional skin was also upregulated (Figure 4c). The induction of cutaneous Treg by SB was also confirmed in situ by immunofluorescence analysis. In lesional and nonlesional psoriatic skin, a lower number of FOXP3+ cells was detected than in healthy controls. SB treatment resulted in an increased number of FOXP3+ cells in skin explants (Figure 4d). To characterize FOXP3+ cells more precisely, double staining with CD25 was performed, revealing that the majority of FOXP3+ cells were also CD25+ (Figure 4e). Likewise, double staining with CD3 indicated that the majority of FOXP3+ cells also expressed CD3 (Supplementary Figure S2). There is evidence that the suppressive activity of Treg is also under epigenetic control (Kitagawa and Sakaguchi, 2017Kitagawa Y. Sakaguchi S. Molecular control of regulatory T cell development and function.Curr Opin Immunol. 2017; 49: 64-70Crossref PubMed Scopus (77) Google Scholar). These epigenetic mechanisms include histone modifications and can cause alterations in gene expression and chromatin remodeling. To analyze the modification of histones, we isolated Treg from PBMC from healthy controls and patients with psoriasis. Histones were isolated and subjected to an antibody-based colorimetric assay for the measurement of the acetylation of H3 histones. Acetylation of H3 histones derived from Treg of patients with psoriasis was significantly decreased compared with the H3 histones obtained from the Treg of healthy controls (Figure 5a). Histone acetylation was upregulated by SB, implying that SB may act as a histone deacetylation inhibitor. For the suppressive activity of Treg, IL-10 is essentially required, whereas IL-6 and IL-17 impede this process. To analyze the expression of these cytokines, skin biopsies were obtained from lesional and nonlesional psoriatic skin. After, the dissection half of each biopsy was treated topically with SB or vehicle. After 12 hours, RNA was isolated, and qRT-PCR was performed. As a control, cytokine transcription of biopsies of normal skin was used and set as 1. IL-17 and IL-6 transcripts were upregulated in lesional psoriatic skin but reduced by SB. In contrast, both cytokines were only minimally expressed in nonlesional psoriatic skin (Figure 5b and c). The expression of IL-10 was lower both in the lesional and nonlesional skin of patients with psoriasis than in the skin of controls but upregulated by SB (Figure 5d). Together, these findings imply that SB is able to correct the disturbed cytokine balance in psoriasis. Psoriasis is driven by complex pathogenesis in which numerous cellular components and mediators are involved. Currently, the IL-23/T helper type 1/ IL-17 axis is regarded as the most relevant player in the pathogenesis (Hawkes et al., 2018Hawkes J.E. Yan B.Y. Chan T.C. Krueger J.G. Discovery of the IL-23/IL-17 Signaling pathway and the treatment of psoriasis.J Immunol. 2018; 201: 1605-1613Crossref PubMed Scopus (270) Google Scholar). Hence, many therapeutic strategies target this axis with impressive clinical results. However, it is unclear whether this axis is autonomously enhanced or whether downregulating mechanisms have lost their taming role. In the latter scenario, Treg play an important role. Treg can be regarded as occasionally harmful components of the immune system because they can inhibit a protective immune response, as best demonstrated in tumor immunology where Treg suppress the immune reaction of the host against the tumor cells and thus support tumor growth (Jacobs et al., 2012Jacobs J.F. Nierkens S. Figdor C.G. de Vries I.J. Adema G.J. Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy?.Lancet Oncol. 2012; 13: e32-e42Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar). Accordingly, suppression of Treg activity, for example, by the application of checkpoint inhibitors has shown impressive antitumor responses (Ugurel et al., 2017Ugurel S. Röhmel J. Ascierto P.A. Flaherty K.T. Grob J.J. Hauschild A. et al.Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update.Eur J Cancer. 2017; 83: 247-257Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). In turn, it has been recognized that Treg play an important physiological role in preventing autoimmune diseases and shutting off inflammatory reactions at the right time point. Accordingly, impairment of Treg has been demonstrated in a variety of autoimmune dermatoses (Loser and Beissert, 2012Loser K. Beissert S. Regulatory T cells: banned cells for decades.J Invest Dermatol. 2012; 132: 864-871Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). There are studies that have demonstrated a decrease in Treg frequencies in the peripheral blood and also in psoriatic lesions. In addition, some studies found dysfunction of Treg in psoriasis (Sugiyama et al., 2005Sugiyama H. Gyulai R. Toichi E. Garaczi E. Shimada S. Stevens S.R. et al.Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation.J Immunol. 2005; 174: 164-173Crossref PubMed Scopus (490) Google Scholar, Wang et al., 2008Wang H. Peters T. Sindrilaru A. Kess D. Oreshkova T. Yu X.Z. et al.TGF-β-dependent suppressive function of Tregs requires wild-type levels of CD18 in a mouse model of psoriasis.J Clin Invest. 2008; 118: 2629-2639Crossref PubMed Scopus (53) Google Scholar). Bovenschen et al., 2011Bovenschen H.J. van de Kerkhof P.C. van Erp P.E. Woestenenk R. Joosten I. Koenen H.J. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin.J Invest Dermatol. 2011; 131: 1853-1860Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar observed that Treg from psoriatic lesions can differentiate toward T helper type 17 cells, which express Foxp3 but produce IL-17A and IL-22. Recently, it was shown in the IMQ model that Treg play an important role in taming the inflammatory response because depletion of Treg resulted in an exacerbation of the inflammation (Hartwig et al., 2018Hartwig T. Zwicky P. Schreiner B. Yawalkar N. Cheng P. Navarini A. et al.Regulatory T cells restrain pathogenic T helper cells during skin inflammation.Cell Rep. 2018; 25: 3564-3572Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, Stockenhuber et al., 2018Stockenhuber K. Hegazy A.N. West N.R. Ilott N.E. Stockenhuber A. Bullers S.J. et al.Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I-driven CD8+ T cell response.J Exp Med. 2018; 215: 1987-1998Crossref PubMed Scopus (35) Google Scholar). Depletion of Treg induced IFN-I and IFN-I–stimulated gene expression and caused accumulation of CD8+ T cells in lesional skin (Stockenhuber et al., 2018Stockenhuber K. Hegazy A.N. West N.R. Ilott N.E. Stockenhuber A. Bullers S.J. et al.Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I-driven CD8+ T cell response.J Exp Med. 2018; 215: 1987-1998Crossref PubMed Scopus (35) Google Scholar). In addition, upon Treg depletion, granulocyte-macrophage colony-stimulating factor producing CD4+ T cells migrated into lesional skin (Hartwig et al., 2018Hartwig T. Zwicky P. Schreiner B. Yawalkar N. Cheng P. Navarini A. et al.Regulatory T cells restrain pathogenic T helper cells during skin inflammation.Cell Rep. 2018; 25: 3564-3572Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Although the latter two studies indicate a taming role of Treg in psoriasis, it was not studied whether activation of Treg can reduce psoriatic inflammation. Hence, we studied whether this can be achieved by SB. We did not only analyze skin and blood samples from patients with psoriasis and healthy controls but also utilized IMQ-induced inflammation (van der Fits et al., 2009van der Fits L. Mourits S. Voerman J.S.A. Kant M. Boon L. Laman J.D. et al.Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.J Immunol. 2009; 182: 5836-5845Crossref PubMed Scopus (1363) Google Scholar). IMQ induced an inflammatory response characterized by thickening of the skin, erythema, and scales. Enhanced expression of IL-17 was detected as well as reduction of IL-10 and Foxp3, implying a reduction of Treg by IMQ. The topical application of IMQ even caused a systemic inflammatory response, which was associated with pronounced splenomegaly. As in the skin, a higher frequency of IL-17–expressing cells and lower frequencies of IL-10– and Foxp3-expressing cells were found. Similar findings were observed in humans; a lower frequency of Foxp3-expressing cells was detected in the blood of patients with psoriasis than in that of controls. In addition, Treg isolated from patients with psoriasis were impaired in their suppressive activity. The same pattern was observed in the skin in situ. The number of Treg was decreased in lesional and, though to a lesser extent, nonlesional skin. This correlated with the cytokine expression levels, showing increased expression of IL-17 and IL-6 and reduced expression of IL-10. In this context, it is important to mention that IL-6 is regarded as a master switch dictating whether the immune response is dominated by pro-inflammatory T helper type 17 cells or protective Treg (Bettelli et al., 2006Bettelli E. Carrier Y. Gao W. Korn T. Strom T.B. Oukka M. et al.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.Nature. 2006; 441: 235-238Crossref PubMed Scopus (5579) Google Scholar). Because the latter analysis was done with skin samples, we cannot discern whether the cytokine alterations observed, especially those observed upon administration of SB, are a direct effect of Treg or indirect through other cells. This is a limitation of the ex vivo approach. Together, these data indicate an alteration both in the number and function of Treg. Thus, our findings join the group of studies that described the alteration of Treg in psoriasis. However, one has to be aware that this alteration is certainly not the only mechanism being involved and it is still unclear whether alteration of Treg is a cause or consequence of the many other pathophysiological events in psoriasis. For example, on one hand, diminished expression of IL-10 can result in a decreased frequency of Treg, and on the other hand, a reduced numbe" @default.
• W3035563103 created "2020-06-19" @default.
• W3035563103 creator A5019087013 @default.
• W3035563103 creator A5045696724 @default.
• W3035563103 creator A5056032249 @default.
• W3035563103 date "2021-01-01" @default.
• W3035563103 modified "2023-10-03" @default.
• W3035563103 title "Induction of Regulatory T Cells and Correction of Cytokine Disbalance by Short-Chain Fatty Acids: Implications for Psoriasis Therapy" @default.
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