Methotrexate inhibition of muropeptide transporter SLC46A2 controls psoriatic skin inflammation
Year: 2022
Type: preprint
Abstract: 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 focus on Slc46a2, which is highly expressed in mammalian epidermal keratinocytes, and show that it is critical for delivery of DAP-muropeptides and activation of NOD1 in keratinocytes, while the related transporter Slc46a3 is critical for responding to MDP, the NOD2 ligand. In a mouse model, Slc46a2 and Nod1 deficiency strongly suppressed psoriatic inflammation, while 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.
Authors: Ravi Bharadwaj, Christina F. Lusi, Siavash Mashayekh, Abhinit Nagar, Malireddi Subbarao, Griffin I. Kane, Kimberly Wodzanowski, Ashley Brown, Kendi Okuda, Amanda Monahan, Donggi Paik, Anubhab Nandy, Madison Anonick, William E. Goldman, Thirumala-Devi Kanneganti, Megan H. Orzalli, Catherine Leimkuhler Grimes, Prabhani U. Atukorale, Neal Silverman
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4298108779