Insulin Treatment Directly Restores Neutrophil Phagocytosis and Bactericidal Activity in Diabetic Mice and Thereby Improves Surgical Site Staphylococcus aureus Infection

Abstract

Bacterial infections, including surgical site infections (SSI), are a common and serious complication of diabetes. Staphylococcus aureus, which is eliminated mainly by neutrophils, is a major cause of SSI in diabetic patients. However, the precise mechanisms by which diabetes predisposes to staphylococcal infection are not fully elucidated. The effect of insulin on this infection is also not well understood. We therefore investigated the effect of insulin treatment on SSI and neutrophil function in diabetic mice. S. aureus was inoculated into the abdominal muscle in diabetic db/db and high-fat-diet (HFD)-fed mice with or without insulin treatment. Although the diabetic db/db mice developed SSI, insulin treatment ameliorated the infection. db/db mice had neutrophil dysfunction, such as decreased phagocytosis, superoxide production, and killing activity of S. aureus; however, insulin treatment restored these functions. Ex vivo treatment (coincubation) of neutrophils with insulin and euglycemic control by phlorizin suggest that insulin may directly activate neutrophil phagocytic and bactericidal activity independently of its euglycemic effect. However, insulin may indirectly restore superoxide production by neutrophils through its euglycemic effect. HFD-fed mice with mild hyperglycemia also developed more severe SSI by S. aureus than control mice and had impaired neutrophil phagocytic and bactericidal activity, which was improved by insulin treatment. Unlike db/db mice, in HFD mice, superoxide production was increased in neutrophils and subsequently suppressed by insulin treatment. Glycemic control by insulin also normalized the neutrophil superoxide-producing capability in HFD mice. Thus, insulin may restore neutrophil phagocytosis and bactericidal activity, thereby ameliorating SSI.T he number of patients with diabetes mellitus has increased greatly worldwide (8,48). It is well known that diabetic patients are more prone to bacterial infections, including surgical site infections (SSI), than healthy individuals. Although many clinical reports have demonstrated that glycemic control reduces the risk of infections, the precise mechanisms by which diabetes predisposes to infections are not well understood (2, 21, 38). Control of bacterial infections has become more important for diabetic patients than in the past, because of the increase in diabetic patients and their susceptibility to infections. Foot infections following skin ulceration are also common causes of hospitalization for diabetic patients (6). These infectious complications seriously impair prognoses for diabetic patients (44).Gram-positive bacteria cause more than half of cases of diabetesrelated wound infections. Especially, Staphylococcus aureus is a major pathogen in these infections (44). Methicillin-resistant S. aureus (MRSA) also has become prevalent among both nosocomial and community-acquired infections in diabetic patients (44). Neutrophils play crucial roles in eliminating bacteria, including S. aureus, from hosts (22). Therefore, neutrophil ...

A Humoral Immune Defect Distinguishes the Response to Staphylococcus aureus Infections in Mice with Obesity and Type 2 Diabetes from That in Mice with Type 1 Diabetes

“…One widely held view is that hyperglycemia is responsible (13). This, however, does not take into account the increased susceptibility of nondiabetic obese and prediabetic patients to S. aureus infection, which suggests alternate or additional risk factors for infection besides hyperglycemia.…”

Mice with Streptozotocin-Induced Hyperglycemia are Susceptible to Invasive Enteric Bacterial Infection

“…3). Previously, PMN cells from diabetic subjects suffering from melioidosis reportedly exhibited decreased phagocytosis and chemotaxis in response to Burkholderia pseudomallei infection (19) as well as the defective release of processed chromatin known as neutrophil extracellular traps, which together resulted in lower bactericidal activity (20). Similarly, monocytes in diabetic patients suffering from tuberculosis, a condition wherein alveolar macrophages and monocytes are vital for containment, displayed impaired chemotaxis in response to the infection and to alveolar macrophages.…”

“…Macrophages, essential immune system components, are involved in 3 fundamental homeostatic activities: host defense, wound healing, and immune regulation. It is generally accepted that phagocytic functions such as chemotaxis, phagocytosis, and respiratory burst are impaired in the polymorphonuclear (PMN) cells and monocytes/macrophages from diabetic individuals compared to those from healthy individuals (17)(18)(19). Accordingly, we isolated peritoneal macrophages from both hyperglycemic and control mice, infected these cells with the pathogenic bacteria described previously, and measured the bactericidal activity of the macrophages across 2 different time intervals.…”

Diabetes Inhibits Gr-1+ Myeloid Cell Maturation viaCebpaDeregulation

“…Db-derived BM Gr-1 + cells perform poorly in functional assays (7,36) and do not promote angiogenesis in vivo (7). Their altered differentiation capacity is shown both in their skewed colony formation (7) and in their hyperpolarization in response to stimuli (5).…”

“…Like myeloid cells from db patients (35), Gr-1 + cells from Lepr db/db mice have an impaired capacity for phagocytosis (36). To examine whether Cebpa induction by G-CSF could rescue this defect, we compared phagocytosis of Alexa Fluor 488-labeled zymosan particles by db-derived Gr-1 + cells cultured for 24 h in the presence and absence of G-CSF.…”