iTRAQ‐based quantitative proteomics reveals biomarkers/pathways in psoriasis that can predict the efficacy of methotrexate

Abstract

Background Methotrexate (MTX) is the first‐line medicine to treat psoriasis. So far, there has been less research on protein biomarkers to predict its efficacy by the proteomic technique. Objectives To evaluate differentially expressed proteins in peripheral mononuclear cells (PBMCs) between good responders (GRs) and non‐responders (NRs) after MTX treatment, compared with normal controls (NCs). Methods We quantified protein expression of PBMCs with four GRs and four NRs to MTX and four NCs by isobaric tags for relative and absolute quantification (iTRAQ), analysing and identifying proteins related to efficacy of MTX in 18 psoriatic patients. Results A total of 3177 proteins had quantitative information, and 403 differentially expressed proteins (fold change ≥1.2, P < 0.05) were identified. Compared to NCs, upregulated proteins (ANXA6, RPS27A, EZR, XRCC6), participating in the activation of NF‐κB, the JAK–STAT pathway and neutrophil degranulation were detected in GRs. The proteins (GPV, FN1, STOM), involving platelet activation, signalling and aggregation as well as neutrophil degranulation were significantly downregulated in GRs. These proteins returned to normal levels after MTX treatment. Furthermore, Western blotting identified the expression of ANXA6 and STAT1 in PBMCs, which were significantly downregulated in GRs, but not in NRs. Conclusions We identified seven differentially expressed and regulated proteins (ANXA6, GPV, FN1, XRCC6, STOM, RPS27A and EZR) as biomarkers to predict MTX efficacy in NF‐κB signalling, JAK–STAT pathways, neutrophil degranulation, platelet activation, signalling and aggregation.

Unlocking the role of the B7‐H4 polymorphism in psoriasis: Insights into methotrexate treatment outcomes: A prospective cohort study

“…In short, platelet activation promotes IL‐17 production by releasing microparticles and forming aggregates with inflammatory cells [49, 51, 52], which further induces platelet activation and contributes to psoriasis development [53]. Our proteomics data indicated that MTX treats psoriasis by modulating neutrophil degranulation and platelet activation, inhibiting the NF‐κB and JAK–STAT pathways [54]. Other studies reported that MTX suppresses T lymphocytes by upregulating negative co‐stimulatory molecules [55].…”

Small-molecule α-lipoic acid targets ELK1 to balance human neutrophil and erythrocyte differentiation

“…Although L-ELK1, but not S-ELK1, significantly upregulated neutrophil activity-related signals (Fig. 5 C), we also found that S-ELK1 significantly upregulated the expression of several neutrophil activity-related genes, including GSN, CTSB, CPNE3 [ 41 ], RAP2B [ 42 ], FCGR2A [ 43 ], HPSE [ 44 ], and modestly upregulated ANXA2, ANXA3 [ 45 ], MOSPD2 [ 46 ], GNS [ 47 ], SDCBP [ 48 ], PAGM1 [ 49 ], HEXB [ 50 ], LAPM2 [ 51 ], STOM [ 52 ], and CR1 [ 53 ] (Fig. 6 A).…”

Pharmaco-Omics in Psoriasis: Paving the Way towards Personalized Medicine

“…Similarly, circulating pathogenic cytokine levels were found to be reduced after methotrexate treatment [ 76 ], as well as lesional chemokine CXCL12 levels [ 77 ], contrary to the upregulated IL-4 interleukin [ 76 ]. Hypothesis-free proteomic analyses have been additionally employed to identify response biomarkers and elucidate the mechanism of action of methotrexate, confirming the molecular reversion of deregulated proteins after administration [ 78 ]. Qiu et al were the first to perform a comprehensive gut microbiome profiling in methotrexate-treated psoriasis patients, attempting to correlate post-treatment microbiome alterations with the blood metabolome [ 79 ].…”