Regulation of Inflammatory Diseases by Solute Carrier Transporters 2266201

Abstract Introduction Cytosolic innate immune sensing is essential for maintaining the integrity of barrier tissues such as the skin and gut. The pattern-recognition receptors NOD1 and NOD2 detect bacterial peptidoglycan fragments (muropeptides) to trigger antimicrobial and inflammatory responses. However, how these muropeptides gain access to the cytosol of epithelial cells has remained unclear. Methods Expression of Slc46a2 and Slc46a3 was analyzed by qRT-PCR, immunofluorescence, and RNA-seq datasets. CRISPR-Cas9—mediated knockout and overexpression studies were performed in epithelial cells to assess NOD1/2 activation using NF-κB reporter, cytokine (IL-8) assays, and labeled muropeptide uptake. Slc46a2⁻/⁻, Slc46a3⁻/⁻, Nod1⁻/⁻, and Nod2⁻/⁻ mice were used in imiquimod-induced psoriasis and DSS or Citrobacter rodentium colitis models. Inflammation and barrier integrity were evaluated by histopathology, cytokine profiling, and immune cell analysis. Results Our study identifies a family of solute carrier transporters, SLC46s, as key mediators of this process. We demonstrate that SLC46A2 and SLC46A3 selectively transport DAP- and MDP-type muropeptides, respectively, thereby triggering cytosolic NOD1 and NOD2 activation in epithelial cells. SLC46A2 is highly expressed in epidermal keratinocytes, where its loss impairs DAP-muropeptide uptake and NOD1-dependent responses, leading to reduced psoriatic inflammation in mice. Conversely, SLC46A3 is expressed in intestinal epithelial cells and is required for MDP transport and NOD2 activation. Slc46a3-deficient mice exhibit increased susceptibility to DSS-induced and Citrobacter rodentium-associated colitis, mirroring the pathology of Nod2-/- animals Conclusion Together, our findings reveal SLC46 transporters as critical gateways for muropeptide entry into epithelial cells, establishing a mechanistic link between microbial sensing and barrier homeostasis, and suggesting novel therapeutic targets for inflammatory skin and intestinal diseases. Funding Source NIH Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)