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Published on: July 6, 2019
MD-2-dependent pulmonary immune responses to inhaled lipooligosaccharides: effect of acylation state
Suzana Hadina1, Jerrold P Weiss, Paul B McCray
1Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA 52242-5000, USA.
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-alpha, macrophage inflammatory protein-1 alpha, IL-6, granulocyte colony-stimulating factor, and IL-1 beta 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.
Insights
Hexa-acylated endotoxins from Neisseria meningitidis cause significant lung inflammation, while penta-acylated forms are less potent. MD-2 is crucial for airway responses to these endotoxins in vivo.
Area of Science:
- Immunology
- Microbiology
- Pulmonary Medicine
Background:
- Endotoxins, potent microbial components, are known to induce pulmonary inflammation.
- Lipooligosaccharides (LOS) from Neisseria meningitidis are key endotoxins with varying acylation states.
- MD-2 is a critical receptor-associated protein in endotoxin recognition.
Purpose of the Study:
- To compare the pulmonary inflammatory potency of wild-type (hexaacylated) and mutant (pentaacylated) Neisseria meningitidis endotoxins (LOS).
- To investigate the role of MD-2 in mediating endotoxin-induced lung inflammation in vivo.
Main Methods:
- Endotoxin-normoresponsive mice (BALB/c) were exposed to penta- and hexaacylated LOS via nasal aspiration.
- Cellular and cytokine/chemokine responses in bronchoalveolar lavage were measured at multiple time points.
- MD-2-null mice were exposed to hexaacylated LOS to assess the impact of MD-2 deficiency.
Main Results:
- Inhalation of hexaacylated LOS induced robust inflammatory responses, including increased neutrophils and cytokines (TNF-alpha, IL-6, IL-1 beta).
- Pentaacylated LOS demonstrated significantly lower inflammatory potency compared to hexaacylated LOS.
- MD-2-null mice exhibited markedly reduced neutrophil infiltration in the lungs after exposure to hexaacylated LOS, indicating MD-2's essential role.
Conclusions:
- The acylation state of Neisseria meningitidis lipooligosaccharides critically influences their inflammatory potency in the lungs.
- MD-2 is essential for effective airway responsiveness to endotoxins, particularly wild-type hexaacylated LOS.
