α1-Acid Glycoprotein Decreases Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice

Abstract

The mechanisms underlying immune deficiency in diabetes are largely unknown. In the present study, we demonstrate that diabetic mice are highly susceptible to polymicrobial sepsis due to reduction in rolling, adhesion, and migration of leukocytes to the focus of infection. In addition, after sepsis induction, CXCR2 was strongly downregulated in neutrophils from diabetic mice compared with nondiabetic mice. Furthermore, CXCR2 downregulation was associated with increased G-protein–coupled receptor kinase 2 (GRK2) expression in these cells. Different from nondiabetic mice, diabetic animals submitted to mild sepsis displayed a significant augment in α1-acid glycoprotein (AGP) hepatic mRNA expression and serum protein levels. Administration of AGP in nondiabetic mice subjected to mild sepsis inhibited the neutrophil migration to the focus of infection, as well as induced l-selectin shedding and rise in CD11b of blood neutrophils. Insulin treatment of diabetic mice reduced mortality rate, prevented the failure of neutrophil migration, impaired GRK2-mediated CXCR2 downregulation, and decreased the generation of AGP. Finally, administration of AGP abolished the effect of insulin treatment in diabetic mice. Together, these data suggest that AGP may be involved in reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice.

Decreased levels of alpha-1-acid glycoprotein are related to the mortality of septic patients in the emergency department

“…Previously, in murine models of sepsis, our group has demonstrated that administration of AGP can inhibit the migration of neutrophils to infectious foci, increasing the mortality of animals (9). Furthermore, we recently demonstrated that increased AGP concentrations observed during diabetes play a role in the high susceptibility to infection in this disease (23). These results are in apparent contradiction with our present data.…”

Role of G protein-coupled receptor kinases in cell migration

“…Higher up-regulation of GRK2 in diabetic mice exacerbated CXCR2 downregulation and reduction of neutrophil migration in sepsis [46]. High GRK2 expression in neutrophils from malaria patients suggests a possible mechanism for an enhanced susceptibility to secondary bacterial infection during malaria [47].…”

Insulin Influences LPS-Induced TNF-α and IL-6 Release Through Distinct Pathways in Mouse Macrophages from Different Compartments

“…Diabetes mellitus was induced via intravenous injection of 60 mg/kg of alloxan monohydrate (Sigma Chemical Co, St. Louis, Mo) dissolved in physiological saline (0.9% NaCl), as previously described [25]. After 10 days, the glycemia of the animals was measured using Accu-Chek Advantage II (Roche Diagnostics, São Paulo, SP, Brazil).…”