MD-2–Dependent Pulmonary Immune Responses to Inhaled Lipooligosaccharides

Abstract

Endotoxins represent one of the most potent classes of microbial immunoactive components that can cause pulmonary inflammation. The aim of this study was to compare the inflammatory potency of two types of Neisseria meningitidis endotoxins (lipooligosaccharides) in lungs: wild type (hexaacylated, LOS wt ) and mutant type (pentaacylated, LOS msbB ), and to determine the importance of MD-2 in endotoxin responses in lungs in vivo. Endotoxin-normoresponsive mice (BALB/c) were exposed to selected doses of penta-and hexaacylated lipooligosaccharides (LOS) by nasal aspiration. Cellular and cytokine/chemokine inflammatory responses in bronchoalveolar lavage were measured at 1-, 4-, 8-, 16-, 24-, and 48-hour time points. MD-2-null mice were exposed to one dose of hexaacylated LOS and inflammatory responses were measured after 4 and 24 hours. Inhalation of hexaacylated LOS resulted in strong inflammatory responses, while pentaacylated LOS was much less potent in inducing increases of neutrophils, TNF-a, macrophage inflammatory protein-1a, IL-6, granulocyte colony-stimulating factor, and IL-1b concentration in bronchoalveolar lavage. Similar kinetics of inflammatory responses in lungs were found in both types of endotoxin exposures. Inhalation of hexaacylated LOS in MD-2-null mice resulted in significantly lower numbers of neutrophils in bronchoalveolar lavage than in normoresponsive mice. Markedly lower inflammatory potency of pentaacylated LOS was observed compared with hexaacylated LOS. Hyporesponsiveness in MD-2-null mice after nasal aspiration of wild-type LOS indicate its essential role in airway responsiveness to endotoxin.

Lack of Lipid A Pyrophosphorylation and Functional lptA Reduces Inflammation by Neisseria Commensals

“…In this study, we postulated that the engagement of the innate immune system of the respiratory tract mucosa by the LOS of commensal Neisseria may elicit a weak response, thereby promoting persistent colonization. This concept is supported by the recent report that meningococcal LOS with hexaacylated LA was significantly more inflammatory in the lungs of an in vivo mouse model than LOS with pentaacylated LA (25). In addition, the study also suggested that, although bacterial products and cytokines can upregulate MD-2, low expression levels of MD-2 in the airway epithelia play a role in the respiratory response to neisserial LOS (29).…”

Endotoxin Exposure: Predictors and Prevalence of Associated Asthma Outcomes in the United States

“…Brix and colleagues suggested that distinct forms of endotoxin may trigger TLR4 differently, with the result that the pentaacylated endotoxin is protective against asthma and allergic sensitization and the more common hexaacylated variety poses increased risk (35). Likewise, Hađina and colleagues noted lower inflammation and differing cytokine profiles in mice exposed to pentaacylated versus hexaacylated forms of endotoxin (36). Predictors of endotoxin in house dust have been examined in several previous studies.…”

The role of innate immunity in occupational allergy: recent findings

“…A study by Hapina et al [34 ] evaluated the dose-dependent pulmonary inflammatory potency of two types of endotoxin from Neisseria meningitides, a lipooligosaccharide (LOS). Wild type hexaacylated endotoxin (LOS wt ) and mutant pentaacylated endotoxin (LOS msbB ) were administered by intranasal inhalation to mice.…”

“…Hadina et al [34 ] then evaluated responsiveness to MD-2 null mice versus MD-2 competent mice. Inhalation of hexaacylated LOS in MD-2 À/À mice failed to induce neutrophil recruitment or cytokine upregulation demonstrating the importance of MD-2 in endotoxin responsiveness in vivo.…”