Methotrexate suppresses psoriatic skin inflammation by inhibiting muropeptide transporter SLC46A2 activity

A closer look at ligand specificity for cellular activation of NOD2 with synthetic muramyl dipeptide analogues

“…Given the low endogenous hPepT1 expression in HEK293T cells, we reasoned that MDP stereoisomers may also enter the cell via passive diffusion, or potentially are taken up by other transporters such as SLC46A3. 16 In either case, the biologically inactive MDP stereoisomers were still able to enter HEK293T cells yet exhibited no NOD2stimulating activity. Consistently, we demonstrated that lipofectamine-facilitated delivery of the MDP stereoisomers into RAW264.7 macrophage cells still failed to trigger proinflammatory cytokines such as TNFa (Fig.…”

Targeting Solute Carrier Transporters (SLCs) as a Therapeutic Target in Different Cancers

“…Organic anion-transporting polypeptides (OATPs) are upregulated in various solid tumors, including liver cancer, with SLCO2A1 (OATP2A1) elevated in HCC and liver metastases from colon cancer, while SLCO1B1 expression decreases in liver cancer, showing a reverse trend with cancer grade [ 128 , 129 ]. There is an increased expression of SLC46A3 reported in HCC patients’ livers [ 12 ]; however, we found that it significantly expresses in the gut region and plays an important role in bacterial muropeptide transportation [ 57 , 130 ].…”

Expanding the Psoriasis Framework: Immunopathogenesis and Treatment Updates

“…18,19 Additionally, patients treated with broad-acting, systemic immunosuppressive medications (eg, cyclosporine, oral corticosteroids) experienced improvement of psoriatic lesions and normalization of the immune infiltrates observed in skin biopsy specimens. 20,21 These early clinical findings led to more sophisticated experimentation in xenotransplant models of psoriasis, 22,23 which explored the clinical efficacy of several less immunosuppressive (eg, methotrexate, anti-tumor necrosis factor [TNF] biologics) 24 or T cell-specific agents (eg, alefacept, abatacept, efalizumab). [25][26][27] The results of these translational studies provided indisputable evidence for the role of the dysregulated immune response as the primary pathogenic process driving plaque formation; they also led to a paradigm shift in how the immunopathogenesis of psoriatic disease was viewed and paved the way for the identification and targeting of other specific proinflammatory signals produced by activated dendritic cell (DC) and T-lymphocyte populations.…”