Chi3l3: a potential key orchestrator of eosinophil recruitment in meningitis induced by Angiostrongylus cantonensis

Shuo Wan,Feng Wu,Xi Sun,Lifu Wang,Zhongdao Wu,Datao Lin,Zilong Yu,Zhengyu Li,Xiaoqiang Sun

doi:10.1186/s12974-018-1071-2

Abstract

BackgroundAngiostrongylus cantonensis, an important foodborne parasite, can induce serious eosinophilic meningitis in non-permissive hosts, such as mouse and human. However, the characteristics and mechanisms of the infection are still poorly understood. This study sought to determine the key molecules and its underlying mechanism in inducing brain eosinophilic infiltration caused by Angiostrongylus cantonensis.MethodsMathematical models were established for prediction of significantly changing genes and the functional associated protein with RNA-seq data in Angiostrongylus cantonensis infection. The expression level of Chi3l3, the predicted key molecule, was verified using Western blotting and real-time quantitative PCR. Critical cell source of Chi3l3 and its relationship with eosinophils were identified with flow cytometry, immunohistochemistry, and further verified by macrophage depletion using liposomal clodronate. The role of soluble antigens of Angiostrongylus cantonensis in eosinophilic response was identified with mice airway allergy model by intranasal administration of Alternaria alternate. The relationship between Chi3l3 and IL-13 was identified with flow cytometry, Western blotting, and Seahorse Bioscience extracellular flux analyzer.ResultsWe analyzed the skewed cytokine pattern in brains of Angiostrongylus cantonensis-infected mice and found Chi3l3 to be an important molecule, which increased sharply during the infection. The percentage of inflammatory macrophages, the main source of Chi3l3, also increased, in line with eosinophils percentage in the brain. Network analysis and mathematical modeling predirect a functional association between Chi3l3 and IL-13. Further experiments verified that the soluble antigen of Angiostrongylus cantonensis induce brain eosinophilic meningitis via aggravating a positive feedback loop between IL-13 and Chi3l3.ConclusionsWe present evidences in favor of a key role for macrophave-derived Chi3l3 molecule in the infection of Angiostrongylus cantonensis, which aggravates eosinophilic meningitis induced by Angiostrongylus cantonensis via a IL-13-mediated positive feedback loop. These reported results constitute a starting point for future research of angiostrongyliasis pathogenesis and imply that targeting chitinases and chitinase-like-proteins may be clinically beneficial in Angiostrongylus cantonensis-induced eosinophilic meningitis.

Highlights

Angiostrongylus cantonensis, an important foodborne parasite, can induce serious eosinophilic meningitis in non-permissive hosts, such as mouse and human
Chi3l3 in mouse brains increased sharply during Angiostrongylus cantonensis/A. cantonensis (AC)-induced eosinophilic meningitis AC induced serious eosinophilic meningitis or meningoencephalitis when mice were infected with the thirdstage larvae (L3) of AC
After 4 days of in vivo exposure to Alternaria and soluble antigens of AC (sAg), we observed an increase in eosinophils of bronchoalveolar lavage (BAL) fluid in C57BL/6 mice from the sAg administration group 2 h after Alternaria treatment (Fig. 3a, b). These results demonstrate that the sAg stimulus may directly or indirectly affect the brain microenvironment during AC-induced eosinophilic meningitis

Summary

Introduction

Angiostrongylus cantonensis, an important foodborne parasite, can induce serious eosinophilic meningitis in non-permissive hosts, such as mouse and human. This study sought to determine the key molecules and its underlying mechanism in inducing brain eosinophilic infiltration caused by Angiostrongylus cantonensis. Angiostrongylus cantonensis (A. cantonensis, AC), a rat lung nematode, is a serious foodborne parasite. It occurs in Asia, the Pacific islands, Australia, and the Caribbean islands [1]. Non-permissive hosts, become infected by eating raw intermediate hosts, including Pomacea canaliculate and Ampullaria crossean [2]. In a prospective descriptive study conducted from June 2008 to January 2014 in a Vietnamese hospital, AC was an important cause of eosinophilic meningitis, accounting for 67.3% (37/55) of cases [7]

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