Surfactant protein A modulates neuroinflammation in adult mice upon pulmonary infection.

ABSTRACT

BACKGROUND: One of the most common entry gates for systemic infection is the lung. In humans, pulmonary infections can lead to significant neurological impairment, ranging from acute sickness behavior to long-term disorders. Surfactant proteins (SP), essential parts of the pulmonary innate immune defense, have been detected in the brain of rats and humans. Recent evidence suggests that SP-A, the major protein component of surfactant, also plays a functional role in modulating neuroinflammation. This study aimed to determine whether SP-A deficiency affects the inflammatory response in the brain of adult mice during pulmonary infection. EXPERIMENTAL PROCEDURE Adult male wild-type (WT, n = 72) and SP-A-deficient (SP-A-/-, n = 72) mice were oropharyngeally challenged with lipopolysaccharide (LPS), Pseudomonas aeruginosa (P. aeruginosa), or PBS (control). Both, behavioral assessment and subsequent brain tissue analysis, were performed 24, 48, and 72 h after challenge. The brain concentrations of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß were determined by ELISA. Quantitative rtPCR was used to detect SP-A mRNA expression in brain homogenates and immunohistochemistry was applied for the detection of SP-A protein expression in brain coronal slices. RESULTS: SP-A mRNA and histological evidence of protein expression were detected in both the lungs and brains of WT mice, with significantly higher amounts in lung samples. SP-A-/- mice exhibited significantly higher baseline concentrations of brain TNF-α, IL-6, and IL-1ß compared to WT mice. Oropharyngeal application of either LPS or P. aeruginosa elicited significantly higher brain levels of TNF-α and IL-1ß in SP-A-/- mice compared to WT mice at all time points. In comparison, behavioral impairment as a measure of sickness behavior, was significantly stronger in WT than in SP-A-/- mice, particularly after LPS application. CONCLUSION: SP-A is known for its anti-inflammatory role in the pulmonary immune response to bacterial infection. Recent evidence suggests that in an abdominal sepsis model SP-A deficiency can lead to increased cytokine levels in the brain. Our results extend this perception and provide evidence for an anti-inflammatory role of SP-A in the brain of adult WT mice after pulmonary infection.