title: CD13 restricts TLR4 endocytic signal transduction in inflammation.
abstract: Dysregulation of the innate immune response underlies numerous pathological conditions. The TLR4 is the prototypical sensor of infection or injury that orchestrates the innate response via sequential activation of both cell surface and endocytic signaling pathways that trigger distinct downstream consequences. CD14 binds and delivers LPS to TLR4 and has been identified as a positive regulator of TLR4 signal transduction. It is logical that negative regulators of this process also exist to maintain the critical balance required for fighting infection, healing damaged tissue, and resolving inflammation. We showed that CD13 negatively modulates receptor-mediated Ag uptake in dendritic cells to control T cell activation in adaptive immunity. In this study, we report that myeloid CD13 governs internalization of TLR4 and subsequent innate signaling cascades, activating IRF-3 independently of CD14. CD13 is cointernalized with TLR4, CD14, and dynamin into Rab5(+) early endosomes upon LPS treatment. Importantly, in response to TLR4 ligands HMGB1 and LPS, p-IRF-3 activation and transcription of its target genes are enhanced in CD13(KO) dendritic cells, whereas TLR4 surface signaling remains unaffected, resulting in a skewed inflammatory response. This finding is physiologically relevant as ischemic injury in vivo provoked identical TLR4 responses. Finally, CD13(KO) mice showed significantly enhanced IFNβ-mediated signal transduction via JAK-STAT, escalating inducible NO synthase transcription levels and promoting accumulation of oxidative stress mediators and tissue injury. Mechanistically, inflammatory activation of macrophages upregulates CD13 expression and CD13 and TLR4 coimmunoprecipitate. Therefore, CD13 negatively regulates TLR4 signaling, thereby balancing the innate response by maintaining the inflammatory equilibrium critical to innate immune regulation.
authors: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030 mghosh@uchc.edu lshapiro@uchc.edu.
authors: Mallika
authors: M
authors: Ghosh
authors: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030.
authors: Jaganathan
authors: J
authors: Subramani
authors: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030.
authors: M Mamunur
authors: MM
authors: Rahman
authors: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030 mghosh@uchc.edu lshapiro@uchc.edu.
authors: Linda H
authors: LH
authors: Shapiro
mesh_terms: D000818:Animals; D018826:CD13 Antigens / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D015870:Gene Expression; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D009573:Nitrites; D051197:Toll-Like Receptor 4; D018826:CD13 Antigens