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IL-4 receptor-alpha-dependent control of Cryptococcus neoformans in the early phase of pulmonary infection
Andreas Grahnert1, Tina Richter1, Daniel Piehler1
1Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
Abstract:
Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised people. Previously we showed that mice succumb to intranasal infection by induction of pulmonary interleukin (IL)-4Rα-dependent type 2 immune responses, whereas IL-12-dependent type 1 responses confer resistance. In the experiments presented here, IL-4Rα⁻/⁻ mice unexpectedly show decreased fungal control early upon infection with C. neoformans, whereas wild-type mice are able to control fungal growth accompanied by enhanced macrophage and dendritic cell recruitment to the site of infection. Lower pulmonary recruitment of macrophages and dendritic cells in IL-4Rα⁻/⁻ mice is associated with reduced pulmonary expression of CCL2 and CCL20 chemokines. Moreover, IFN-γ and nitric oxide production are diminished in IL-4Rα⁻/⁻ mice compared to wild-type mice. To directly study the potential mechanism(s) responsible for reduced production of IFN-γ, conventional dendritic cells were stimulated with C. neoformans in the presence of IL-4 which results in increased IL-12 production and reduced IL-10 production. Together, a beneficial role of early IL-4Rα signaling is demonstrated in pulmonary cryptococcosis, which contrasts with the well-known IL-4Rα-mediated detrimental effects in the late phase.
Insights
Early signaling via interleukin-4 receptor alpha (IL-4Rα) benefits control of Cryptococcus neoformans lung infections by enhancing immune cell recruitment and function, contrasting with its later detrimental effects.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Cryptococcus neoformans is an opportunistic pathogen causing lung inflammation and meningoencephalitis, particularly in immunocompromised individuals.
- Previous studies indicated IL-4Rα-dependent type 2 immunity leads to susceptibility, while IL-12-dependent type 1 immunity confers resistance.
- The role of IL-4Rα in the early stages of pulmonary cryptococcosis remained unclear.
Purpose of the Study:
- To investigate the role of IL-4Rα signaling in the early innate immune response to C. neoformans lung infection.
- To elucidate the mechanisms by which IL-4Rα influences immune cell recruitment and cytokine production during pulmonary cryptococcosis.
Main Methods:
- Comparison of C. neoformans infection outcomes in IL-4Rα knockout mice and wild-type mice.
- Analysis of immune cell populations (macrophages, dendritic cells) at the infection site.
- Measurement of chemokine (CCL2, CCL20) and cytokine (IFN-γ, IL-10, IL-12) expression.
- In vitro stimulation of dendritic cells with C. neoformans and IL-4.
Main Results:
- IL-4Rα knockout mice exhibited reduced fungal control and impaired recruitment of macrophages and dendritic cells compared to wild-type mice.
- Lower expression of CCL2 and CCL20 chemokines was observed in the lungs of IL-4Rα knockout mice.
- Production of IFN-γ and nitric oxide was diminished in IL-4Rα knockout mice.
- In vitro, IL-4 stimulation of dendritic cells enhanced IL-12 production and reduced IL-10 production.
Conclusions:
- Early IL-4Rα signaling plays a beneficial role in controlling C. neoformans lung infections.
- This beneficial effect is mediated by enhanced immune cell recruitment and modulation of cytokine production, including increased IL-12.
- These findings contrast with the known detrimental effects of IL-4Rα in the later stages of pulmonary cryptococcosis.
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