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The IL-33-ILC2 pathway protects from amebic colitis
Md Jashim Uddin1,2, Jhansi L Leslie1, Stacey L Burgess1
1Department of Medicine: Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VA, USA.
Abstract:
Entamoeba histolytica is a pathogenic protozoan parasite that causes intestinal colitis, diarrhea, and in some cases, liver abscess. Through transcriptomics analysis, we observed that E. histolytica infection was associated with increased expression of IL-33 mRNA in both the human and murine colon. IL-33, the IL-1 family cytokine, is released after cell injury to alert the immune system of tissue damage. Treatment with recombinant IL-33 protected mice from amebic infection and intestinal tissue damage; moreover, blocking IL-33 signaling made mice more susceptible to amebiasis. IL-33 limited the recruitment of inflammatory immune cells and decreased the pro-inflammatory cytokine IL-6 in the cecum. Type 2 immune responses were upregulated by IL-33 treatment during amebic infection. Interestingly, administration of IL-33 protected RAG2-/- mice but not RAG2-/-γc-/- mice, demonstrating that IL-33-mediated protection required the presence of innate lymphoid cells (ILCs). IL-33 induced recruitment of ILC2 but not ILC1 and ILC3 in RAG2-/- mice. At baseline and after amebic infection, there was a significantly higher IL13+ILC2s in C57BL/J mice, which are naturally resistant to amebiasis, than CBA/J mice. Adoptive transfer of ILC2s to RAG2-/-γc-/- mice restored IL-33-mediated protection. These data reveal that the IL-33-ILC2 pathway is an important host defense mechanism against amebic colitis.
Insights
Interleukin-33 (IL-33) protects against Entamoeba histolytica infection by activating innate lymphoid cells (ILCs), specifically ILC2s, which are crucial for host defense in amebic colitis.
Area of Science:
- Immunology
- Parasitology
- Molecular Biology
Background:
- Entamoeba histolytica is a protozoan parasite causing intestinal and liver diseases.
- Increased IL-33 mRNA expression is observed in the colon during E. histolytica infection.
- IL-33 is a cytokine released upon cell injury, signaling tissue damage to the immune system.
Purpose of the Study:
- To investigate the role of IL-33 in host defense against E. histolytica infection.
- To elucidate the specific immune cells and pathways involved in IL-33-mediated protection.
Main Methods:
- Transcriptomics analysis to assess gene expression changes during infection.
- In vivo studies using mouse models treated with recombinant IL-33 or IL-33 signaling blockers.
- Experiments with genetically modified mice (RAG2-/-, RAG2-/-γc-/-) and adoptive transfer of innate lymphoid cells (ILCs).
Main Results:
- Recombinant IL-33 treatment protected mice from amebic infection and reduced intestinal damage.
- Blocking IL-33 signaling increased susceptibility to amebiasis, with reduced IL-6 and inflammatory cell recruitment.
- IL-33-mediated protection was dependent on innate lymphoid cells (ILCs), particularly ILC2s, and induced type 2 immune responses.
Conclusions:
- The IL-33-ILC2 pathway is a critical host defense mechanism against amebic colitis.
- IL-33 promotes resistance to Entamoeba histolytica infection by orchestrating ILC2-mediated immune responses.
- ILC2s play a significant role in the natural resistance observed in certain mouse strains.
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