Interleukin-1β Participates in the Development of Pneumococcal Acute Lung Injury and Death by Promoting Alveolar Microvascular Leakage

Abstract

Streptococcus pneumoniae (S. pneumoniae, also known as pneumococcus) infections are major causes of death worldwide. Despite the development and use of effective antibiotics, high, early mortality due to pneumococcal infections has not been decreased for the last few decades. Recent study found a deadly hemorrhagic acute lung injury (ALI) as a major cause of death at the early stage of severe pneumococcal infections. Interleukin (IL)-1β was known to play critical roles not only for the development of ALI but also resolution of it. The role of IL-1β on the pathogenesis of pneumococcal ALI, however, has not been well understood yet. This study aims to investigate the role of IL-1β on the development of pneumococcal ALI and subsequent death. IL-1β expression was upregulated in the lungs of pneumococcal ALI in wild-type (WT) mice, but not in the plasma. Despite an increased expression of pulmonary IL-1β, no inflammatory cell infiltration into airway has been observed. Upregulation of IL-1β expression was indeed dependent on pneumococcal cytoplasmic toxin pneumolysin and its cell surface receptor Toll-like receptor 4. Deficiency of IL-1R1, a cell surface receptor of IL-1β, resulted in a markedly reduced hemorrhagic pulmonary edema and early death in pneumococcal ALI. Finally, IL-1β neutralization in WT mice protects against pulmonary hemorrhagic edema and death. These data suggest that pulmonary expression of IL-1β exacerbates pneumolysin-induced ALI and death by promoting alveolar hemorrhagic edema.