Rhein immunomodulates MAPK/NF-κB axis, protecting against pneumococcal pneumonia in mice

Pneumonia, particularly caused by Streptococcus pneumoniae, remains a leading cause of community-acquired respiratory infections, often leading to severe pulmonary inflammation and tissue damage. Current treatments primarily target bacterial eradication, but often fall short in mitigating the host's excessive inflammatory response. This inflammation is significantly driven by the overexpression of key signaling pathways, specifically the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) cascades. Understanding and modulating these pathways offers a promising therapeutic avenue to reduce lung injury and improve outcomes in pneumococcal pneumonia.

Researchers investigated the immunomodulatory effects of Rhein in a mouse model of Streptococcus pneumoniae-induced pneumonia. Forty male C57BL/6 mice were divided into four groups: healthy control, infected control, and two treatment groups receiving Rhein 10 mg/kg or Rhein 30 mg/kg. Lung wet/dry weight ratio and bacterial load were assessed. Expression levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, MCP-1) and anti-inflammatory IL-10, along with inflammatory enzymes (COX-2, iNOS), were quantified in lung tissues and bronchoalveolar lavage fluid (BALF) using RT-PCR and ELISA. Additionally, ELISA and Western blotting were employed to analyze the phosphorylation status of MAPK and NF-κB proteins.

Rhein treatment significantly attenuated the severity of S. pneumoniae-induced pneumonia. Treated mice exhibited a significant decrease in the lung wet/dry weight ratio, indicating reduced pulmonary edema, and a marked reduction in bacterial load within the lungs. Analysis of inflammatory markers revealed that Rhein downregulated the expression of COX-2 and iNOS. Cytokine profiling further demonstrated that Rhein significantly reduced the levels of key pro-inflammatory mediators, including IL-6, IL-1β, TNF-α, and MCP-1, in both lung tissues and BALF. Simultaneously, an increase in the anti-inflammatory cytokine IL-10 was observed. The underlying mechanism was confirmed through ELISA and Western blotting: Rhein significantly inhibited the phosphorylation of both MAPK and NF-κB signaling proteins. This inhibition directly correlates with the observed reduction in inflammatory responses.

Rhein treatment significantly decreased lung wet/dry weight ratio, reduced bacterial load, and downregulated pro-inflammatory cytokines while increasing anti-inflammatory IL-10 by inhibiting MAPK and NF-κB phosphorylation.