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Alveolar macrophage deactivation in murine septic peritonitis: role of interleukin 10
R C Reddy1, G H Chen, M W Newstead
1Division of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0360, USA.
Abstract:
Sepsis predisposes the host to a number of infectious sequelae, particularly the development of nosocomial pneumonia. Mechanisms by which sepsis results in impairment of lung antibacterial host defense have not been well defined. Alveolar macrophages (AM) represent important immune effector cells of the lung airspace. In this study, we examined the effects of cecal ligation and puncture (CLP) on murine AM function ex vivo, including the expression of proinflammatory cytokines and AM phagocytic activity. AM were harvested from mice subjected to a sham operation and CLP 24 h after laparotomy, adherence purified, and challenged with lipopolysaccharide (LPS) or left unstimulated. Both unstimulated and LPS-stimulated AM from mice subjected to CLP (CLP mice) produced significantly smaller amounts of proinflammatory cytokines tumor necrosis factor alpha and interleukin (IL-12) and C-X-C chemokines KC and macrophage inflammatory protein 2 than similarly treated AM from animals subjected to a sham operation. Furthermore, AM isolated from CLP mice displayed a marked impairment in phagocytic activity, as determined by flow cytometry, with this defect persisting to 48 h post-CLP. Induction of peritoneal sepsis syndrome resulted in a time-dependent increase in IL-10 in plasma and peritoneal fluid. Interestingly, the impairment in AM proinflammatory-cytokine production and phagocytic activity observed in AM from CLP mice was partially reversed by the in vivo neutralization of IL-10 prior to AM harvest. These observations suggest that abdominal sepsis syndrome results in significant impairment in AM effector cell function, which is mediated, in part, by sepsis-induced expression of IL-10.
Insights
Sepsis impairs lung immune cells called alveolar macrophages (AM), reducing their ability to fight infection. This dysfunction is partly caused by increased interleukin-10 (IL-10) during sepsis.
Area of Science:
- Immunology
- Microbiology
- Pathophysiology
Background:
- Sepsis increases susceptibility to infections like pneumonia.
- Mechanisms impairing lung antibacterial defenses during sepsis are unclear.
- Alveolar macrophages (AM) are key immune cells in the lung airspace.
Purpose of the Study:
- To investigate the impact of sepsis on murine alveolar macrophage (AM) function.
- To assess AM proinflammatory cytokine production and phagocytic activity post-sepsis.
- To explore the role of interleukin-10 (IL-10) in sepsis-induced AM dysfunction.
Main Methods:
- Cecal ligation and puncture (CLP) model used to induce sepsis in mice.
- Alveolar macrophages (AM) harvested 24-48 hours post-CLP or sham operation.
- AM function assessed ex vivo, including cytokine production (LPS-stimulated) and phagocytosis via flow cytometry.
- Plasma and peritoneal fluid analyzed for IL-10 levels.
- In vivo IL-10 neutralization tested for reversal of AM dysfunction.
Main Results:
- AM from CLP mice produced significantly lower levels of proinflammatory cytokines (TNF-α, IL-12) and chemokines (KC, MIP-2) compared to sham controls.
- AM from CLP mice exhibited impaired phagocytic activity, persisting up to 48 hours post-CLP.
- Sepsis induction led to a time-dependent increase in IL-10 in plasma and peritoneal fluid.
- In vivo IL-10 neutralization partially restored AM cytokine production and phagocytic function.
Conclusions:
- Abdominal sepsis significantly impairs alveolar macrophage (AM) effector functions, including cytokine release and phagocytosis.
- Sepsis-induced interleukin-10 (IL-10) plays a partial role in mediating this AM dysfunction.
- Understanding these mechanisms is crucial for developing strategies against sepsis-associated pneumonia.