236ba53a83c200de70de0d0ae510a802 pmc_34944673.pdf 3c1505e1c93f25c32f4843a675e0ce413ecfac95 pmc_34944673.pdf d6b34b468963b1223560a2bbd93b8f4a09b44908793d32f18c7ba20d8176d806 pmc_34944673.pdf Title: Thalidomide Exerts Anti-Inflammatory Effects inCutaneous Lupus by Inhibiting the IRF4/NF-ҡ-.4B and AMPK1/mTOR Pathways Subject: Thalidomide is effective in patients with refractory cutaneous lupus erythematosus (CLE). However, the mechanism of action is not completely understood, and its use is limited by its potential, severe side-effects. Immune cell subset analysis in thalidomide’s CLE responder patients showed a reduction of circulating and tissue cytotoxic T-cells with an increase of iNKT cells and a shift towards a Th2 response. We conducted an RNA-sequencing study using CLE skin biopsies performing a Therapeutic Performance Mapping System (TMPS) analysis in order to generate a predictive model of its mechanism of action and to identify new potential therapeutic targets. Integrating RNA-seq data, public databases, and literature, TMPS analysis generated mathematical models which predicted that thalidomide acts via two CRBN-CRL4A- (CRL4CRBN) dependent pathways: IRF4/NF-ҡB and AMPK1/mTOR. Skin biopsies showed a significant reduction of IRF4 and mTOR in post-treatment samples by immunofluorescence. In vitro experiments confirmed the effect of thalidomide downregulating IRF4 in PBMCs and mTOR in keratinocytes, which converged in an NF-ҡB reduction that led to a resolution of the inflammatory lesion. These results emphasize the anti-inflammatory role of thalidomide in CLE treatment, providing novel molecular targets for the development of new therapies that could avoid thalidomide’s side effects while maintaining its efficacy. Keywords: cutaneous lupus; thalidomide; mechanism of action; new therapy Author: Sandra Domingo, Cristina Solé, Teresa Moliné, Berta Ferrer and Josefina Cortés-Hernández Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Dec 9 07:23:25 2021 CET ModDate: Thu Dec 9 07:53:30 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4379124 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- FCPWLZ+VnURWPalladioL Type 1 Custom yes yes no 10 0 GZXPZV+SFRM0900 Type 1 Custom yes yes no 15 0 THOERC+URWPalladioL-Ital Type 1 Custom yes yes no 20 0 NALOSN+URWPalladioL-Bold Type 1 Custom yes yes no 25 0 HYFROV+URWPalladioL-Roma Type 1 Custom yes yes no 29 0 FKDZCG+SFRM1728 Type 1 Custom yes yes no 33 0 GIFXFT+VnURWPalladioL-Bold Type 1 Custom yes yes no 37 0 LDHOPF+SFRM0700 Type 1 Custom yes yes no 41 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 71 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 75 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 79 0 QIXIWU+SFRM1000 Type 1 Custom yes yes no 91 0 COGLGI+CMSY10 Type 1 Builtin yes yes no 95 0 JDWIZJ+EURM10 Type 1 Builtin yes yes no 99 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 109 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 121 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 125 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 129 0 ABCDEE+Palatino Linotype,Italic CID TrueType Identity-H yes yes yes 133 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 149 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 153 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 157 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 161 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 177 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 181 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 185 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 189 0 DUJUUF+PazoMath-Italic Type 1 Builtin yes yes no 201 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 209 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 213 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 217 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 221 0 ABCDEE+Palatino Linotype,Italic CID TrueType Identity-H yes yes yes 228 0 Times New Roman,Italic CID TrueType Identity-H yes no yes 235 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 252 0 Times New Roman CID TrueType Identity-H yes no yes 256 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 264 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 268 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 272 0 ABCDEE+Palatino Linotype,Italic CID TrueType Identity-H yes yes yes 279 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 295 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 299 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 303 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 307 0 ABCDEE+Palatino Linotype,Italic CID TrueType Identity-H yes yes yes 314 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 329 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 333 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 337 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 341 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 364 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 368 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 372 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 376 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-03-22 02:26:43 CET RepresentationInformation: pmc_34944673.pdf ReportingModule: BYTESTREAM, Rel. 1.4 (2018-10-01) LastModified: 2022-01-10 07:57:59 CET Size: 4379124 Format: bytestream Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/octet-stream Checksum: 6b786b6f Type: CRC32 Checksum: 236ba53a83c200de70de0d0ae510a802 Type: MD5 Checksum: 3c1505e1c93f25c32f4843a675e0ce413ecfac95 Type: SHA-1