Diabetes Exacerbates Infection via Hyperinflammation by Signaling through TLR4 and RAGE
Travis B. Nielsen,
Paul Pantapalangkoor,
Jun Yan,
Brian M. Luna,
Ken Dekitani,
Kevin Bruhn,
Brandon Tan,
Justin Junus,
Robert A. Bonomo,
Ann Marie Schmidt,
Michael Everson,
Frederick Duncanson,
Terence M. Doherty,
Lin Lin,
Brad Spellberg
Affiliations
Travis B. Nielsen
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA
Paul Pantapalangkoor
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA
Jun Yan
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA
Brian M. Luna
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA
Ken Dekitani
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA
Kevin Bruhn
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA
Brandon Tan
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA
Justin Junus
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA
Robert A. Bonomo
Departments of Medicine, Pharmacology and Molecular Biology and Microbiology, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, Ohio, USA
Ann Marie Schmidt
Departments of Medicine, Biochemistry and Molecular Pharmacology and Pathology, New York University, New York, New York, USA
Michael Everson
Eisai, Inc., Tokyo, Japan
Frederick Duncanson
Eisai, Inc., Tokyo, Japan
Terence M. Doherty
Los Angeles Biomedical Research Institute, Torrance, California, USA
Lin Lin
Los Angeles Biomedical Research Institute, Torrance, California, USA
Brad Spellberg
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA
ABSTRACT For more than a century, diabetic patients have been considered immunosuppressed due to defects in phagocytosis and microbial killing. We confirmed that diabetic mice were hypersusceptible to bacteremia caused by Gram-negative bacteria (GNB), dying at inocula nonlethal to nondiabetic mice. Contrary to the pervasive paradigm that diabetes impedes phagocytic function, the bacterial burden was no greater in diabetic mice despite excess mortality. However, diabetic mice did exhibit dramatically increased levels of proinflammatory cytokines in response to GNB infections, and immunosuppressing these cytokines with dexamethasone restored their resistance to infection, both of which are consistent with excess inflammation. Furthermore, disruption of the receptor for advanced glycation end products (RAGE), which is stimulated by heightened levels of AGEs in diabetic hosts, protected diabetic but not nondiabetic mice from GNB infection. Thus, rather than immunosuppression, diabetes drives lethal hyperinflammation in response to GNB by signaling through RAGE. As such, interventions to improve the outcomes from GNB infections should seek to suppress the immune response in diabetic hosts. IMPORTANCE Physicians and scientists have subscribed to the dogma that diabetes predisposes the host to worse outcomes from infections because it suppresses the immune system. This understanding was based largely on ex vivo studies of blood from patients and animals with diabetes. However, we have found that the opposite is true and worse outcomes from infection are caused by overstimulation of the immune system in response to bacteria. This overreaction occurs by simultaneous ligation of two host receptors: TLR4 and RAGE. Both signal via a common downstream messenger, MyD88, triggering hyperinflammation. In summary, contrary to hundred-year-old postulations about immune suppression in diabetic hosts, we find that diabetes instead predisposes to more severe infections because of additional inflammatory output through dual activation of MyD88 by not only TLR4 but also RAGE. It is the activation of RAGE during GNB infections in those with diabetes that accounts for their heightened susceptibility to infection compared to nondiabetic hosts.
