Exudate macrophages attenuate lung injury by the release of IL-1 receptor antagonist in gram-negative pneumonia.

RATIONALE: Exudate macrophages are key players in host defense toward invading pathogens. Their antiinflammatory and epithelial-protective potential in gram-negative pneumonia, however, remains elusive. OBJECTIVES: We investigated whether exudate macrophages contributed to preservation of alveolar epithelial barrier integrity and analyzed the molecular pathways involved. METHODS: We evaluated the antiinflammatory and epithelial-protective effects of exudate macrophages in a model of LPS- and Klebsiella pneumoniae-induced lung injury comparing wild-type and CC-chemokine receptor 2 (CCR2)-deficient mice with defective lung macrophage recruitment and in in vitro studies using primary alveolar epithelial cells. MEASUREMENTS AND MAIN RESULTS: CCR2(-/-) mice exhibited enhanced alveolar epithelial cell apoptosis and lung leakage on intratracheal LPS treatment, which could be attributed to lack of exudate macrophage recruitment from the circulating pool as demonstrated in a model of wild-type/CCR2(-/-) bone-marrow chimeric mice. Among various antiinflammatory and proliferative mediators analyzed, the endogenous counterpart of resident macrophage-expressed IL-1beta, IL-1 receptor antagonist (IL-1ra), was highly up-regulated in flow-sorted exudate macrophages in LPS-treated wild-type mice. LPS/IL-1beta-induced impairment of alveolar epithelial cell integrity was antagonized by IL-1ra in vitro. Finally, intratracheal substitution of IL-1ra or intravenous adoptive transfer of IL-1ra(+/+) but not IL-1ra(-/-) blood mononuclear cells attenuated alveolar inflammation, epithelial apoptosis, and loss of barrier function in LPS-challenged or K. pneumoniae-infected CCR2(-/-) mice and enhanced survival after K. pneumoniae infection. CONCLUSIONS: We conclude that recruited lung macrophages attenuate IL-1beta-mediated acute lung injury in gram-negative pneumonia by release of IL-1ra.

Herold S, Tabar TS, Janssen H, Hoegner K, Cabanski M, Lewe-Schlosser P, Albrecht J, Driever F, Vadasz I, Seeger W, Steinmueller M, Lohmeyer J.

Am J Respir Crit Care Med, 2011. 183(10): 1380-90.