| First Author | Prantner D | Year | 2021 |
| Journal | J Leukoc Biol | Volume | 109 |
| Issue | 3 | Pages | 605-619 |
| PubMed ID | 32678947 | Mgi Jnum | J:303675 |
| Mgi Id | MGI:6509521 | Doi | 10.1002/JLB.3A0520-745RR |
| Citation | Prantner D, et al. (2021) Classically activated mouse macrophages produce methylglyoxal that induces a TLR4- and RAGE-independent proinflammatory response. J Leukoc Biol 109(3):605-619 |
| abstractText | The highly reactive compound methylglyoxal (MG) can cause direct damage to cells and tissues by reacting with cellular macromolecules. MG has been identified as a biomarker associated with increased sepsis-induced mortality. Patients undergoing septic shock have significantly elevated circulating MG levels compared to postoperative patients and healthy controls. Furthermore, MG has been implicated in the development of type II diabetes mellitus and Alzheimer's disease. Because MG is generated during glycolysis, we hypothesized that MG may be produced by classically activated (M1) macrophages, possibly contributing to the inflammatory response. LPS and IFN-gamma-treated macrophages acquired an M1 phenotype (as evidenced by M1 markers and enhanced glycolysis) and formed MG adducts, MG-H1, MG-H2, and MG-H3, which were detected using antibodies specific for MG-modified proteins (methylglyoxal 5-hydro-5-methylimidazolones). MG adducts were also increased in the lungs of LPS-treated mice. Macrophages treated with LPS and IFN-gamma also exhibited decreased expression of glyoxalase 1 (Glo1), an enzyme that metabolizes MG. Concentrations of exogenous, purified MG > 0.5 mM were toxic to macrophages; however, a nontoxic dose of 0.3 mM induced TNF-alpha and IL-1beta, albeit to a lesser extent than LPS stimulation. Despite prior evidence that MG adducts may signal through "receptor for advanced glycation endproducts" (RAGE), MG-mediated cell death and cytokine induction by exogenous MG was RAGE-independent in primary macrophages. Finally, RAGE-deficient mice did not exhibit a significant survival advantage following lethal LPS injection. Overall, our evidence suggests that MG may be produced by M1 macrophages during sepsis, following IFN-gamma-dependent down-regulation of Glo1, contributing to over-exuberant inflammation. |
