Broad Infiltration of Macrophages Leads to a Proinflammatory State in Streptozotocin-Induced Hyperglycemic Mice.
Chronic diseases are often associated with altered inflammatory response, leading to increased host vulnerability to new inflammatory challenges. Employing streptozotocin (STZ)-induced diabetes as a model, we further investigate mechanisms leading to enhanced neutrophil (polymorphonuclear leukocytes [PMN]) responses under hyperglycemia and compare them with those under chronic colitis. We show that, different from colitis under which the PMN response is significantly potentiated, the existence of a proinflammatory state associated with broad increases in macrophages in various organs plays a dominant role in promoting the PMN inflammatory response in diabetic mice. Studies of PMN infiltration during zymosan-induced peritonitis reveal that hyperglycemia enhances PMN recruitment not through inducing a high level of IL-17, which is the case in colitis, but through increasing F4/80+macrophages in the peritoneal cavity, resulting in elevations of IL-6, IL-1β, TNF-α, and CXCL1 production. Insulin reversal of hyperglycemia, but not the neutralization of IL-17, reduces peritoneal macrophage numbers and ameliorates PMN infiltration during peritonitis. Significantly increased macrophages are also observed in the liver, kidneys, and intestines under hyperglycemia, and they are attributable to exacerbated nephropathy and colitis when inflammatory conditions are induced by doxorubicin and dextran sulfate sodium, respectively. Furthermore, analyses of monocyte production and macrophage proliferation in tissues suggest that significant monocytosis of inflammatory F4/80+Gr-1+monocytes from the spleen and macrophage proliferation in situ synergistically contribute to the increased macrophage population under hyperglycemia. In conclusion, our results demonstrate that STZ-induced hyperglycemic mice develop a systemic proinflammatory state mediated by broad infiltration of macrophages.
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30302.
Shuo
S
Niu
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30302.
Zhen
Z
Bian
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30302.
Alexandra
0000-0002-7176-3764
A
Tremblay
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30302.
Youqun
Y
Luo
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30302.|Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854; and.
Koby
K
Kidder
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30302.
Ahmed
0000-0002-4698-3220
A
Mansour
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30302.|State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.
Ke
K
Zen
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30302; yliu@gsu.edu.
Yuan
Y
Liu
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000276:immunology*; D004195:Disease Models, Animal; D006943:Hyperglycemia / Q000139:chemically induced / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009504:Neutrophils / Q000276:immunology; D013311:Streptozocin
D020381:Interleukin-17; D013311:Streptozocin