The IL-33-ILC2 pathway protects from amebic colitis

Md Jashim Uddin,Julio Revilla,Stacey L Burgess,Pankaj Kumar,Noah Oakland,Mayuresh Abhyankar,Jhansi L Leslie,Brandon Thompson,Alyse Frisbee,Alexandra N Donlan,William A Petri Jr

doi:10.1038/s41385-021-00442-2

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.

Highlights

Diarrhea-related illnesses are one of the major causes of death worldwide in children under 5 years of age, resulting in approximately 500,000 mortalities annually[1]
One of the significantly upregulated genes was Il33 (Fig. 1a), encoding for the cytokine IL-33, which is known as a nuclear alarmin and an inducer of type 2 immune responses
We first tested if IL-33 was increased in the intestinal tissue upon E. histolytica infection in the mouse model of amebiasis

Summary

INTRODUCTION

Diarrhea-related illnesses are one of the major causes of death worldwide in children under 5 years of age, resulting in approximately 500,000 mortalities annually[1]. Intestinal tissue damage by E. histolytica is associated with the production of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, IFN-γ, and TNFα7. These proinflammatory cytokines may in part affect susceptibility by regulating the recruitment of neutrophils and macrophages, cells that have been shown to be critical in protection from amebiasis in a mouse model[8]. Complex interdependent collaborations between intestinal epithelial cells and immune cells dictate the outcome of E. histolytica infection Understanding these interactions is critical to finding an effective intervention for amebiasis. 1234567890();,: Fig. 1 Amebic infection induces IL-33 expression in the colon of humans and mice and upregulates host immune-related pathways in colonic tissue. We observed that IL-33 did not require the presence of T and B cells to confer protection from amebic colitis, did require ILC2s

RESULTS

DISCUSSION

METHODS