| First Author | Arora S | Year | 2011 |
| Journal | Infect Immun | Volume | 79 |
| Issue | 5 | Pages | 1915-26 |
| PubMed ID | 21383052 | Mgi Jnum | J:171937 |
| Mgi Id | MGI:5002419 | Doi | 10.1128/IAI.01270-10 |
| Citation | Arora S, et al. (2011) Effect of Cytokine Interplay on Macrophage Polarization during Chronic Pulmonary Infection with Cryptococcus neoformans. Infect Immun 79(5):1915-26 |
| abstractText | 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-gamma(-/-)) 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-gamma regulate the polarization state of Macs in this model. A higher IL-4/IFN-gamma ratio leads to the development of alternatively activated Macs (aaMacs), whereas a higher IFN-gamma/IL-4 ratio leads to the generation of classically activated Macs (caMacs). WT mice that coexpress IL-4 and IFN-gamma during fungal infection concurrently display both types of Mac polarization markers. Concurrent stimulation of Macs with IFN-gamma 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. |
