The Dual Benefit of Sulfasalazine on Pneumocystis Pneumonia-Related Immunopathogenesis and Antifungal Host Defense Does Not Require IL-4Rα-Dependent Macrophage Polarization

Pneumocystis is a respiratory fungal pathogen that is among the most frequent causes of life-threatening pneumonia (PcP) in immunocompromised hosts. Alveolar macrophages play an important role in host defense against Pneumocystis, and several studies have suggested that M2 polarized macrophages have anti-Pneumocystis effector activity. Our prior work found that the immunomodulatory drug sulfasalazine (SSZ) provides a dual benefit during PcP-related immune reconstitution inflammatory syndrome (IRIS) by concurrently suppressing immunopathogenesis while also accelerating macrophage-mediated fungal clearance. The benefits of SSZ were associated with heightened Th2 cytokine production and M2 macrophage polarization. Therefore, to determine whether SSZ improves the outcome of PcP through a mechanism that requires Th2-dependent M2 polarization, RAG2(-/-) mice lacking interleukin 4 receptor alpha chain (IL-4R alpha) on macrophage lineage cells were generated. As expected, SSZ treatment dramatically reduced the severity of PcP-related immunopathogenesis and accelerated fungal clearance in immune-reconstituted RAG2(-/-) mice. Similarly, SSZ treatment was also highly effective in immune-reconstituted RAG2/IL-4R alpha(-/-) and RAG2/gamma interferon receptor (IFN-gamma R)(-/-) mice, demonstrating that neither IL-4R alpha-dependent M2 nor IFN-gamma R-dependent M1 macrophage polarization programs were required for the beneficial effects of SSZ. Despite the fact that macrophages from RAG2/IL-4R alpha(-/-) mice could not respond to the Th2 cytokines IL-4 and IL-13, M2-biased alveolar macrophages were identified in the lungs following SSZ treatment. These data demonstrate that not only does SSZ enhance phagocytosis and fungal clearance in the absence of macrophage IL-4R alpha signaling, but also that SSZ promotes M2 macrophage polarization in an IL-4R alpha-independent manner. These findings could have implications for the treatment of PcP and other diseases in which M2 polarization is beneficial. Pneumocystis is a respiratory fungal pathogen that is among the most frequent causes of life-threatening pneumonia (PcP) in immunocompromised hosts. Alveolar macrophages play an important role in host defense against Pneumocystis, and several studies have suggested that M2 polarized macrophages have anti-Pneumocystis effector activity.

Automated summary

Pneumocystis is a respiratory fungal pathogen that causes life-threatening pneumonia in immunocompromised hosts. M2 polarized macrophages have been found to be effective against Pneumocystis. The drug sulfasalazine has shown dual benefits in immune reconstitution inflammatory syndrome by suppressing immunopathogenesis and accelerating fungal clearance.