| First Author | Casteel JL | Year | 2022 |
| Journal | Front Immunol | Volume | 13 |
| Pages | 867082 | PubMed ID | 35720381 |
| Mgi Jnum | J:326110 | Mgi Id | MGI:7293513 |
| Doi | 10.3389/fimmu.2022.867082 | Citation | Casteel JL, et al. (2022) Modification of Extracellular Matrix by the Product of DHA Oxidation Switches Macrophage Adhesion Patterns and Promotes Retention of Macrophages During Chronic Inflammation. Front Immunol 13:867082 |
| abstractText | Oxidation of polyunsaturated fatty acids contributes to different aspects of the inflammatory response due to the variety of products generated. Specifically, the oxidation of DHA produces the end-product, carboxyethylpyrrole (CEP), which forms a covalent adduct with proteins via an -amino group of lysines. Previously, we found that CEP formation is dramatically increased in inflamed tissue and CEP-modified albumin and fibrinogen became ligands for alphaDbeta2 (CD11d/CD18) and alphaMbeta2 (CD11b/CD18) integrins. In this study, we evaluated the effect of extracellular matrix (ECM) modification with CEP on the adhesive properties of M1-polarized macrophages, particularly during chronic inflammation. Using digested atherosclerotic lesions and in vitro oxidation assays, we demonstrated the ability of ECM proteins to form adducts with CEP, particularly, DHA oxidation leads to the formation of CEP adducts with collagen IV and laminin, but not with collagen I. Using integrin alphaDbeta2-transfected HEK293 cells, WT and alpha D - / - mouse M1-polarized macrophages, we revealed that CEP-modified proteins support stronger cell adhesion and spreading when compared with natural ECM ligands such as collagen IV, laminin, and fibrinogen. Integrin alphaDbeta2 is critical for M1 macrophage adhesion to CEP. Based on biolayer interferometry results, the isolated alphaD I-domain demonstrates markedly higher binding affinity to CEP compared to the "natural" alphaDbeta2 ligand fibrinogen. Finally, the presence of CEP-modified proteins in a 3D fibrin matrix significantly increased M1 macrophage retention. Therefore, CEP modification converts ECM proteins to alphaDbeta2-recognition ligands by changing a positively charged lysine to negatively charged CEP, which increases M1 macrophage adhesion to ECM and promotes macrophage retention during detrimental inflammation, autoimmunity, and chronic inflammation. |
