Interleukin-6-Driven Inflammatory Response Induces Retinal Pathology in a Model of Ocular Toxoplasmosis Reactivation

Abstract

c Ocular inflammation is one of the consequences of infection with the protozoan parasite Toxoplasma gondii. Even if lesions are self-healing in immunocompetent persons, they pose a lifetime risk of reactivation and are a serious threat to vision. As there are virtually no immunological data on reactivating ocular toxoplasmosis, we established a model of direct intravitreal injection of parasites in previously infected mice with a homologous type II strain. Two different mouse strains with variable ability to control retinal infection were studied in order to describe protective and deleterious reaction patterns. In Swiss-Webster mice, which are already relatively resistant to primary infection, no peak of parasite load was observed upon reinfection. In contrast, the susceptible inbred strain C57BL/6 showed high parasite loads after 7 days, as well as marked deterioration of retinal architecture. Both parameters were back to normal on day 21. C57BL/6 mice also reacted with a strong local production of inflammatory and Th1-type cytokines, like interleukin-6 (IL-6), IL-17A, and gamma interferon (IFN-␥), while Swiss-Webster mice showed only moderate expression of the Th2 cytokine IL-31. Interestingly, rapid intraocular production of anti-Toxoplasma antibodies was observed in Swiss-Webster but not in C57BL/6 mice. We then localized the cellular source of different immune mediators within the retina by immunofluorescence. Finally, neutralization experiments of IFN-␥ or IL-6 demonstrated the respective protective and deleterious roles of these cytokines for parasite control and retinal integrity during reinfection. In conclusion, we developed and immunologically characterized a promising mouse model of reactivating ocular toxoplasmosis. O cular toxoplasmosis (OT), a sequel of infection with the apicomplexan parasite Toxoplasma gondii, is a major cause of visual impairment worldwide, responsible for 30 to 50% of posterior uveitis in immunocompetent people. While OT was considered until recently as being exclusively due to congenital infection, screening of Toxoplasma-seropositive persons in Europe and North America revealed that 1 to 2% of this population presents retinal toxoplasmic lesions (1). Thus, possible reactivation of these ocular infections in postnatally infected individuals poses a hitherto underestimated problem for the health systems in these countries (2) and even more so in regions like South America (3, 4). At the moment, no treatment has so far achieved a consistently reduced risk of reactivation, except perhaps in high-risk patients (5, 6). To establish more specific, immune-based interventions, we need to elucidate the physiopathology of OT, which is so far largely ignored. Therefore, we wanted to gather novel data on the immune responses involved in retinal T. gondii reactivation. The long-term objective of this model is to open new therapeutic perspectives of human OT.The main obstacle for thorough research of ocular reactivation is the absence of a suitable mouse model (4). After oral or intraper...

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“…cereus intraocular infection. On the other hand, another study reported a substantial role for IL-6 in the retinal inflammatory response in a mouse ocular toxoplasmosis reactivation model ( Rochet et al, 2015 ). In our study, IL-6 and other chemokines also increased during C .…”

The broad-spectrum chemokine inhibitor NR58-3.14.3 modulates macrophage-mediated inflammation in the diseased retina

“…A pathogenic role of Il6 is more recently highlighted by Levy and colleagues, who show that accumulation of the AMD biomarker apolipoprotein E (APOE) in subretinal macrophages up-regulates their expression of Il6, which in turn promotes their increased survival and induction of retinal pathology in light-damaged Cx3cr1−/− mice [ 59 ]. Additionally, a deleterious role of Il6 has been characterised in experimental ocular toxoplasmosis via antibody neutralisation, which considerably improved retinal morphology compared to controls [ 74 ].…”

Toxoplasma gondii seroprevalence varies by cat breed

“…Host-parasite relationships and coevolution have influenced the balance between the hosts and the parasite, susceptibility of the hosts, and virulence of the parasite [1,2]. Host species [8][9][10][11], breeds [12,13], strains [14][15][16][17], and families [18] display apparent differences in their susceptibility to the infection. The differences appear genetic [5,6] and may be explained by differences in the immune responses elicited [19,20].…”