Identification and characterization of microglia/macrophages in the granuloma microenvironment of encephalic schistosomiasis japonicum

Abstract

BackgroundEgg-induced immune response and granuloma formation are thought to be the basis of central nervous system (CNS)-related clinical symptoms of Schistosoma japonicum. Microglia/macrophages are the major immune cells involved in detection and subsequent elimination of pathogens and injured tissue in the brain. However, little is known about their role in the pathogenesis of neuroschistosomiasis. The main purpose of the study is to clarify the pathological involvement of microglia/macrophages in the pathogenesis of neuroschistosomiasis (NS).MethodsStaining techniques were applied to the granuloma tissues excised from 4 patients, as well as mice model which was established by microinjecting viable S. japonicum eggs into the brain. Clinical features of the patients and neurological symptoms in mice were also collected and analyzed in terms of their correlation with microglia/macrophages.ResultsMicroglia/macrophages constituted the major portions of the granulomas surrounding the eggs in both all human cases and S. japonicum egg-injected mice. Granuloma persisted in all patients accompanied by unremitted neurological symptoms, while in mice granuloma formation initiated on day 3, peaked on day 7 and subsided on day 30 post injection with S. japonicum eggs. No neurological abnormalities were observed in egg-injected mice except for significant weight decrease on day 3 compared with saline-injected control. M1 polarization of microglia/macrophages was confirmed in egg-injected mice 3 days post injection and in all human cases. M2 polarization was absent in human patients despite the duration of complaints but dominated in the whole progression of egg-induced pathology in mice until the elimination of eggs and subsidence of neuroinflammation on day 30 post injection.ConclusionsMicroglia/macrophages participated actively in the granuloma microenvironment of encephalic schistosomiasis japonicum in both human and mice. The polarization pattern of microglia/macrophages coincided with the symptomatic features in human cases and S. japonicum egg-injected mice, indicating M2 instead of M1 activation as a probably more important mediator in the battle against egg-induced pathology and concomitant manifestations. These new findings will shed light on the pathogenesis of NS from a brand-new perspective, and may contribute to the immunotherapy development for such disease, favoring perhaps M2 polarization of microglia/macrophages as a feasible strategy.

Roles of TLR7 in Schistosoma japonicum Infection-Induced Hepatic Pathological Changes in C57BL/6 Mice

“…IL-6 and IL-10 are important proinflammatory cytokines and antiinflammatory cytokines, respectively (Kumar et al, 2021). Higher numbers of macrophages were found in the livers of infected WT and TLR7 KO mice, which expressed higher levels of CD86 and secreted more IL-4, IL-10, and IL-12, suggesting that macrophages played an important role in the progression of S. japonicum infection-induced hepatitis, as previously reported (Tan et al, 2019;Ye et al, 2020). Although the number of macrophages in the livers of infected TLR7 KO mice was similar to that in infected WT mice, they expressed lower CD86 levels and produced fewer cytokines.…”

The microbiota–microglia axis in central nervous system disorders

“…Schistosoma japonicum (S. japonicum), prevalent in Southeast Asia, mainly affects the brain (encephalic schistosomiasis japonicum) (223,224). A recent study has shown that CNS macrophages including microglia play a role in forming granulomas that isolate and neutralize the infecting parasite eggs (225). Interestingly, another study utilizing mice with S. japonicum ova-induced granulomas has shown alterations in the intestinal barrier and the gut microbiota composition upon infection (226).…”

Neuroimmunology of Common Parasitic Infections in Africa

“…Schistosoma eggs secrete antigens such as glycans and glycoproteins that elicit an immune response leading to granuloma formation ( 230 , 233 , 236 ). In both human cases with neuroschistosomiasis caused by S. japonicum and mice that were injected with S. japonicum eggs in the brain microglia/macrophages constituted the major components of the granulomas surrounding the eggs ( 237 ). Patients with spinal cord schistosomiasis have increased levels of IL-1beta, IL-4, IL-6 and IL-10 and low concentrations of TNF-α and IFN-γ in both CSF and serum ( 238 ).…”