RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

Abstract

The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor capable of recognizing multiple pathogen-associated and dangerassociated molecular patterns that contributes to the initiation and potentiation of inflammation in many disease processes. During infection, RAGE functions to either exacerbate disease severity or enhance pathogen clearance depending on the pathogen studied. Acinetobacter baumannii is an opportunistic human pathogen capable of causing severe infections, including pneumonia and sepsis, in impaired hosts. The role of RAGE signaling in response to opportunistic bacterial infections is largely unknown. In murine models of A. baumannii pneumonia, RAGE signaling alters neither inflammation nor bacterial clearance. In contrast, RAGE Ϫ/Ϫ mice systemically infected with A. baumannii exhibit increased survival and reduced bacterial burdens in the liver and spleen. The increased survival of RAGE Ϫ/Ϫ mice is associated with increased circulating levels of the anti-inflammatory cytokine interleukin-10 (IL-10). Neutralization of IL-10 in RAGE Ϫ/Ϫ mice results in decreased survival during systemic A. baumannii infection that mirrors that of wild-type (WT) mice, and exogenous IL-10 administration to WT mice enhances survival in this model. These findings demonstrate the role for RAGE-dependent IL-10 suppression as a key modulator of mortality from Gram-negative sepsis.KEYWORDS Acinetobacter baumannii, IL-10, innate immunity, pneumonia, RAGE, receptor for advanced glycation end products, sepsis A n effective immune response to an invading pathogen depends upon host recognition of the infecting organism and resultant initiation of an immune response. This process is accomplished through the recognition of pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs) (1). Signaling downstream of PRRs, including Toll-like receptors (TLRs), activates transcription factors such as nuclear factor kappa B (NF-B), inducing expression of proinflammatory genes and thereby altering cytokine and chemokine production, resulting in inflammation and effector cell recruitment to the site of infection (1, 2). In addition to PAMPs, many PRRs have also evolved to detect altered host proteins, referred to as danger-associated molecular patterns (DAMPs) (3). The signaling mechanisms required to initiate an appropriate response to an invading pathogen may also potentiate inflammation during the course of infection, and this inflammatory response may enhance tissue damage and exacerbate disease (4). The maladaptive potentiation of inflammation in response to infection is responsible for many of the severe manifestations of infectious

IL-10 Protects Mice From the Lung Infection of Acinetobacter baumannii and Contributes to Bacterial Clearance by Regulating STAT3-Mediated MARCO Expression in Macrophages

“…Intranasal administration of γIL-10 or adoptive transfer of macrophages capable of producing IL-10 improved mice survival and promoted bacterial clearance in IL-10-deficient mice. Consistent with a study by Noto et al (14), our results clearly indicated that IL-10 has beneficial effects on host defenses against pulmonary infection with A. baumannii. Neutrophils and macrophages are known to play important roles in host resistance to pulmonary infection with A. baumannii (26,27).…”

“…A recent study showed that the receptor for advanced glycation end products (RAGE) suppressed IL-10 production in a systemic infection model of A. baumannii, which resulted in increased mortality of the infected mice, although the RAGE signaling did not affect lung inflammation or bacterial clearance when the mice were intranasally infected (14). Administration of recombinant IL-10 rescued wild type (WT) mice from A. baumannii-induced lethality (14), suggesting that IL-10 may play a beneficial role in host defenses against A. baumannii infection. However, there is no evidence on the role of IL-10 in host protection against lung infections with A. baumannii, and the underlying mechanism is still unclear.…”

Ager Deletion Enhances Ischemic Muscle Inflammation, Angiogenesis, and Blood Flow Recovery in Diabetic Mice

“…In this context, a burgeoning body of evidence links RAGE to opposing outcomes in murine models of infection challenge. For example, whereas deletion of Ager in Streptococcus pneumoniae pneumonia or Acinetobacter baumanii sepsis resulted in improved survival and diminished tissue damage, 61, 62 Ager deletion in a distinct setting of Klebsiella pneumoniae was detrimental to survival and recovery 63 . These considerations underscore the complexities of RAGE in the immune and vascular response to imposed stresses.…”

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

“…MLCK -/-mice were given either exogenous IL10 (20 μg; BioLegend) or vehicle via intraperitoneal injection immediately after the onset of sepsis utilizing a published protocol (48). Mice were treated with fluids, antibiotics and pain medicine and followed 7 d for survival.…”