GM-CSF Administration Improves Defects in Innate Immunity and Sepsis Survival in Obese Diabetic Mice

Abstract

Sepsis is the leading cause of death in the intensive care unit with an overall mortality rate of 20%. Individuals who are obese and have type 2 diabetes have increased recurrent, chronic, nosocomial infections that worsen the long-term morbidity and mortality from sepsis. Additionally, animal models of sepsis have shown that obese, diabetic mice have lower survival rates compared with nondiabetic mice. Neutrophils are essential for eradication of bacteria, prevention of infectious complications, and sepsis survival. In diabetic states, there is a reduction in neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) generation; however, few studies have investigated the extent to which these deficits compromise infection eradication and mortality. Using a cecal ligation and puncture model of sepsis in lean and in diet-induced obese mice, we demonstrate that obese diabetic mice have decreased "emergency hematopoiesis" after an acute infection. Additionally, both neutrophils and monocytes in obese, diabetic mice have functional defects, with decreased phagocytic ability and a decreased capacity to generate ROS. Neutrophils isolated from obese diabetic mice have decreased transcripts of Axl and Mertk, which partially explains the phagocytic dysfunction. Furthermore, we found that exogenous GM-CSF administration improves sepsis survival through enhanced neutrophil and monocytes phagocytosis and ROS generation abilities in obese, diabetic mice with sepsis.Abbreviations used in this article: CLP, cecal ligation and puncture; DIO, dietinduced obese; ICU, intensive care unit; M1, proinflammatory macrophage; M2, anti-inflammatory macrophage; MFI, mean fluorescence intensity; qPCR, quantitative PCR; ROS, reactive oxygen species; T2D, type 2 diabetes.

A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity

“…Unlike extracellular ROS, intracellular ROS is most often reported to be significantly decreased in neutrophils in studies of T1D or T2D, which is thought to contribute to susceptibility to infection (Table 2) (49,154,170). This was demonstrated in both a model of S. aureus hind paw infection in leptin deficient diabetic mice, and a model of polymicrobial bacterial sepsis in obese diet-induced diabetic mice (model of T2D) (65,109). Reduced levels of ROS were associated with lower bacterial clearance and increased mortality (65,109).…”

“…Research aiming to therapeutically modify neutrophil function in response to infection in T1D or T2D lags compared to the volume of studies reporting observational differences between those with and without diabetes. However, research aiming to restore aberrant neutrophil function in diabetes is gaining momentum in the field, with a focus on modifying neutrophil ROS production and NETosis to improve infection outcomes (64)(65)(66)(67). The enhanced susceptibility in PWD to COVID-19 infection has garnered global interest during the ongoing COVID-19 pandemic and approaches to improve neutrophil responses in people with diabetes might have important therapeutic potential (68)(69)(70).…”

The Essential Involvement of the Omentum in the Peritoneal Defensive Mechanisms During Intra-Abdominal Sepsis

“…The neutrophil is a key component of innate immunity and is required for the survival of sepsis patients ( 17 ). Rapid recruitment of neutrophils to the sites of infection is critical for bacterial containment and eradication ( 18 ).…”

“…To effectively eliminate the pathogen, neutrophils are required to phagocytize the bacteria and destroy them after engulfment. It is worth noting that the host cells can release ROS in phagosomes and ultimately eliminate the pathogens ( 17 ). In the present study, neutrophils were isolated from the peritoneal cavity, and their phagocytic ability and ROS production were assessed using flow cytometric analysis.…”

“Shielding” of Cytokine Induction by the Periodontal Microbiome in Patients with Periodontitis Associated with Type 2 Diabetes Mellitus

“…the comorbidities under study has been obtained, since exogenous administration of GM-CSF increases the survival rate of experimental animals [56]. Next, the profile of four proinflammatory cytokines was analyzed: three of these cytokines are secreted mainly by innate immune cells (primarily by the macrophages IL-1β, IL-6, and TNFα), while IL-17A is a secretion product of Th17, one of the subtypes of T-helper cells (Fig.…”