Journal
INFECTION AND IMMUNITY
Volume 79, Issue 5, Pages 1915-1926Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.01270-10
Keywords
-
Categories
Funding
- NHLBI [R01-HL65912, R01-HL63670]
- VA Merit Review grants
Ask authors/readers for more resources
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 interferondeficient (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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available