甲氨蝶呤
炎症
银屑病
药理学
生物
癌症研究
免疫学
作者
Ravi Bharadwaj,Christina F Lusi,Siavash Mashayekh,Abhinit Nagar,Malireddi Subbarao,Griffin Kane,Kimberly A. Wodzanowski,Ashley R. Brown,Kendi Okuda,Amanda J. Monahan,Donggi Paik,Anubhab Nandy,Madison V Anonick,William E. Goldman,Thirumala‐Devi Kanneganti,Megan H. Orzalli,Catherine L. Grimes,Prabhani U. Atukorale,Neal S. Silverman
出处
期刊:Immunity
[Elsevier]
日期:2023-05-01
卷期号:56 (5): 998-1012.e8
被引量:6
标识
DOI:10.1016/j.immuni.2023.04.001
摘要
Summary
Cytosolic innate immune sensing is critical for protecting barrier tissues. NOD1 and NOD2 are cytosolic sensors of small peptidoglycan fragments (muropeptides) derived from the bacterial cell wall. These muropeptides enter cells, especially epithelial cells, through unclear mechanisms. We previously implicated SLC46 transporters in muropeptide transport in Drosophila immunity. Here, we focused on Slc46a2, which was highly expressed in mammalian epidermal keratinocytes, and showed that it was critical for the delivery of diaminopimelic acid (DAP)-muropeptides and activation of NOD1 in keratinocytes, whereas the related transporter Slc46a3 was critical for delivering the NOD2 ligand MDP to keratinocytes. In a mouse model, Slc46a2 and Nod1 deficiency strongly suppressed psoriatic inflammation, whereas methotrexate, a commonly used psoriasis therapeutic, inhibited Slc46a2-dependent transport of DAP-muropeptides. Collectively, these studies define SLC46A2 as a transporter of NOD1-activating muropeptides, with critical roles in the skin barrier, and identify this transporter as an important target for anti-inflammatory intervention.
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