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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.
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Figure 1.
IL-1β expression is upregulated in the lungs of pneumococcal ALI, but not in the plasma. A, BALB/c and C57BL/6 mice were intratracheally (i.t.) inoculated with pneumococcal D39 lysate equivalent to the 5 × 107 colony forming unit (CFU), and mRNA expression of IL-1β was measured from the lungs of mice 3 hours after i.t. inoculation by real-time quantitative PCR (Q-PCR) assay. B, C57BL/6 mice were i.t. inoculated with various amount of pneumococcal D39 lysate (equivalent to 0.625 ~ 5 × 107 CFU), and mRNA expression of IL-1β was measured from the lungs of mice 3 hours after i.t. inoculation by Q-PCR assay. C, BALB/c mice were i.t. inoculated with pneumococcal D39 lysate, and protein expression of IL-1β was measured from the BALF and plasma of mice 3 hours after i.t. inoculation by ELISA assay. D, C57BL/6 mice were i.t. inoculated with pneumococcal D39 lysate, and bronchoalveolar lavage (BAL) was conducted 3 hours after i.t. inoculation. Cell numbers in the BAL fluid (BALF) were counted. Data are the means ± SD. ∗, p <0.05 compared with CON; ∗∗, p < 0.01 compared with CON. CON, control.
Figure 2.
Pneumococcal pneumolysin-induced upregulation of pulmonary IL-1β is dependent on a cellular TLR4. A, C57BL/6 mice were i.t. inoculated with pneumococcal D39 lysate, D39-PLN, or pneumolysin (PLY), and mRNA expression of IL-1β was measured from the lungs of mice 3 hours after i.t. inoculation by Q-PCR assay. B & C, C57BL/6 mice were i.t. inoculated with pneumococcal D39 lysate, D39-PLN, or PLY, and protein expression of IL-1β was measured from the BALF (B) and plasma (C) of mice 3 hours after i.t. inoculation by ELISA assay. D, TLR4-/- mice were i.t. inoculated with pneumococcal D39 lysate, and expression levels of IL-1β mRNA were compared to those of genetic background control BALB/c mice by Q-PCR assay. Data are the means ± SD. ∗, p < 0.01 compared with CON; ∗∗, p < 0.05 compared with D39 (A-C); ∗∗∗, p < 0.05 compared with D39 BALB/c mice. CON, control; PLY, pneumolysin.
Figure 3.
Deficiency of IL-1R1 protects mice against pneumococcal ALI and death. A-C, IL-1R1-/- and control C57BL/6 mice were i.t. inoculated with pneumococcal D39 lysate, and lung extravascular water weight (A), alveolar protein permeability (B), and alveolar hemoglobin (C) were measured from the lungs of mice 3 hours after i.t. inoculation. D, IL-1R1-/- and control C57BL/6 mice were i.t. inoculated with pneumococcal D39 lysate, and survival rates were recorded for 5 days. Viability in D was assessed by using Kaplan-Meier survival analysis and compared by long-lank test. Data are the means ± SD. ∗, p < 0.01 compared with CON in C57BL/6; ∗∗, p < 0.05 compared with D39 in C57BL/6 mice. CON, control.
Figure 4.
Pulmonary neutralization of IL-1β inhibited pneumococcal ALI and death in WT mice. A, C57BL/6 mice were i.t. inoculated with 100 μg of anti-mouse IL-1β antibody or control IgG, and pneumococcal D39 lysate were i.t. inoculated 2 hours after antibody inoculation. Survival rates were recorded for 5 days, and viability was assessed by using Kaplan-Meier survival analysis. B-D, C57BL/6 mice were i.t. inoculated with 100 μg of anti-mouse IL-1β antibody for 2 hours followed by i.t. inoculation of pneumococcal D39 lysate. Lung extravascular water weight (B), alveolar protein permeability (C), and alveolar hemoglobin (D) were measured from the lungs of mice 3 hours after i.t. inoculation of D39. Data in B – D are the means ± SD. ∗, p < 0.01 compared with CON in WT mice treated with Con IgG; ∗∗, p < 0.05 compared with D39 in WT mice treated with Con IgG. CON, control.
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