Administration of IL-23 engages innate and adaptive immune mechanisms during fungal infection

Area of Science:

• Immunology
• Infectious Diseases
• Cytokine Signaling

Background:

• Interleukin-23 (IL-23) is a critical cytokine implicated in driving chronic inflammatory responses.
• Chronic cryptococcosis, caused by Cryptococcus neoformans, remains a significant global health challenge, necessitating novel therapeutic strategies.
• The pro-inflammatory capacity of IL-23 raises questions about its potential therapeutic application in infectious diseases.

Purpose of the Study:

• To investigate whether the pro-inflammatory properties of IL-23 can be therapeutically utilized to combat chronic cryptococcosis.
• To evaluate the impact of IL-23 administration on survival, fungal burden, and immune cell dynamics during Cryptococcus neoformans infection.

Main Methods:

• Murine model of chronic cryptococcosis induced by Cryptococcus neoformans infection.
• Treatment with recombinant IL-23 and comparison with IL-12 treatment.
• Analysis of cytokine profiles, inflammatory infiltrate composition (T cells, dendritic cells), and immune cell markers (CD86) in infected tissues.
• Assessment of IL-17A and IL-22 production in both T-cell-sufficient and T-cell-deficient mice.

Main Results:

• IL-23 treatment resulted in prolonged survival and reduced fungal burden in mice infected with Cryptococcus neoformans, though it was less effective than IL-12.
• IL-23 administration induced significant alterations in cytokine profiles and inflammatory cell composition, including recruitment of T cells and dendritic cells.
• Distinct from endogenous IL-23/IL-12 pathways, IL-23 treatment promoted hallmarks of the T helper 17 (Th17) pathway, with non-T cells contributing to IL-17A and IL-22 production.
• In T-cell-deficient mice, IL-23 treatment enhanced IL-17A and IL-22 production and modulated the cellular response, increasing CD86 expression on macrophages.

Conclusions:

• IL-23 treatment can induce both innate and adaptive inflammatory responses at the site of infection.
• Despite inducing inflammation, IL-23 demonstrated a limited impact on overall resistance to chronic cryptococcosis compared to IL-12.
• The findings suggest that while IL-23 modulates immune responses, its therapeutic efficacy in this model of chronic fungal infection is suboptimal.