Effect of cytokine interplay on macrophage polarization during chronic pulmonary infection with Cryptococcus neoformans.

Abstract

The immune response to Cryptococcus neoformans following pulmonary infection of C57BL/6 wild-type (WT) mice results in the development of persistent infection with characteristics of allergic bronchopulmonary mycosis (ABPM). To further clarify the role of Th1/Th2 polarizing cytokines in this model, we performed kinetic analysis of cytokine responses and compared cytokine profiles, pathologies, and macrophage (Mac) polarization status in C. neoformans-infected WT, interleukin-4-deficient (IL-4(-/-)), and gamma interferon-deficient (IFN-γ(-/-)) C57BL/6 mice. Results show that cytokine expression in the infected WT mice is not permanently Th2 biased but changes dynamically over time. Using multiple Mac activation markers, we further demonstrate that IL-4 and IFN-γ regulate the polarization state of Macs in this model. A higher IL-4/IFN-γ ratio leads to the development of alternatively activated Macs (aaMacs), whereas a higher IFN-γ/IL-4 ratio leads to the generation of classically activated Macs (caMacs). WT mice that coexpress IL-4 and IFN-γ during fungal infection concurrently display both types of Mac polarization markers. Concurrent stimulation of Macs with IFN-γ and IL-4 results in an upregulation of both sets of markers within the same cells, i.e., formation of an intermediate aaMac/caMac phenotype. These cells express both inducible nitric oxide synthase (important for clearance) and arginase (associated with chronic/progressive infection). Together, our data demonstrate that the interplay between Th1 and Th2 cytokines supports chronic infection, chronic inflammation, and the development of ABPM pathology in C. neoformans-infected lungs. This cytokine interplay modulates Mac differentiation, including generation of an intermediate caMac/aaMac phenotype, which in turn may support chronic "steady-state" fungal infection and the resultant ABPM pathology.

• Authors: Shikha Arora, Michal A Olszewski, Tiffany M Tsang, Roderick A McDonald, Galen B Toews, Gary B Huffnagle
• Journal: Infection and immunity (Infect Immun) Vol. 79 Issue 5 Pg. 1915-26 (May 2011) ISSN: 1098-5522 [Electronic] United States
• PMID: 21383052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cytokines
• Interleukin-4

Topics

• Animals
• Cryptococcosis (immunology, pathology)
• Cryptococcus neoformans (immunology)
• Cytokines (immunology)
• Female
• Fluorescent Antibody Technique
• Immunohistochemistry
• Interleukin-4 (deficiency)
• Lung Diseases, Fungal (immunology, pathology)
• Macrophage Activation (immunology)
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• Reverse Transcriptase Polymerase Chain Reaction
• Th1 Cells (immunology)
• Th2 Cells (immunology)