Functional analysis of myeloid cell populations in Toxoplasma encephalitis
Final Report Abstract
Alongside with brain resident immune cells, infiltrating Ly6ChiCCR2+ monocytes play a decisive role in host defense upon chronic cerebral Toxoplasma gondii infection. We have detected, that depletion of this particular monocyte subset resulted in elevated parasite load in the brain and decreased survival of infected mice. Notably, Ly6ChiCCR2+ monocytes directed parasite control due to production of proinflammatory mediators, such as IL-1α, IL-1β, IL-6, inducible NO synthase, TNF, and reactive oxygen intermediate. Interestingly, Ly6ChiCCR2+ monocytes were capable to produce the regulatory cytokine IL-10 upon certain stimuli, revealing their unique plasticity. Moreover, we confirmed by adoptive transfer that the recruited monocytes are able to further develop into two distinct subpopulations contributing to parasite control and profound host defense. Besides, we have shown that the recruitment of Ly6Chi monocytes to the central nervous system (CNS) is regulated by P-selectin glycoprotein ligand-1. These results indicate the critical importance of recruited Ly6Chi monocytes upon chronic cerebral toxoplasmosis and reveal the behavior of further differentiated myeloidderived mononuclear cell subsets in parasite control and immune regulation of the CNS. Latent T. gondii infection is frequent in the elderly, and it has been suggested that CNS infections may influence the course of Alzheimer's disease. Therefore, in addition to the planned experiments we investigated how chronic T. gondii infection and resulting neuroinflammation can affect β-amyloid (Aβ) plaque deposition and removal in a mouse model of Alzheimer's disease. Importantly, the chronic infection was associated with reduced Aβ and plaque load in 5xFAD mice. Upon infection, myeloid-derived CCR2hiLy6Chi monocytes, CCR2+Ly6Cint, and CCR2+ Ly6Clo mononuclear cells were recruited to the brain of mice. Compared to microglia, these recruited mononuclear cells showed highly increased phagocytic capacity of Aβ ex vivo. The F4/80+ Ly6Clo macrophages expressed high levels of Triggering Receptor Expressed on Myeloid cells 2 (TREM2), CD36, and Scavenger Receptor A1 (SCARA1), indicating phagocytic activity. Importantly, selective ablation of CCR2+Ly6Chi monocytes resulted in an increased amount of Aβ in infected mice. Elevated insulin-degrading enzyme (IDE), matrix metalloproteinase 9 (MMP9), as well as immunoproteasome subunits β1i/LMP2, β2i/MECL-1, and β5i/LMP7 mRNA levels in the infected brains indicated increased proteolytic Aβ degradation. Particularly, LMP7 was highly expressed by the recruited mononuclear cells in the brain, suggesting a novel mechanism of Aβ clearance. Our results indicate that chronic T. gondii infection ameliorates β-amyloidosis in a murine model of Alzheimer's disease by activation of the immune system, specifically by recruitment of Ly6Chi monocytes and by enhancement of phagocytosis and degradation of soluble Aβ.
Publications
- Spinal cord pathology in chronic experimental Toxoplasma gondii infection. Eur. J. Microbiol. Immunol. 2014. 4(1)65-75
Möhle L, Parlog A, Pahnke J, Dunay IR
(See online at https://doi.org/10.1556/EuJMI.4.2014.1.6) - Ly6Chi monocytes control cerebral Toxoplasmosis. J. Immunology. 2015 Apr.
Biswas A, Bruder D, Wolf SA, Jeron A, Mack M, Heimesaat MM, Dunay IR
(See online at https://doi.org/10.4049/jimmunol.1402037) - Specific Depletion of Ly6C hi Inflammatory Monocytes Prevents Immunopathology in Experimental Cerebral Malaria Plos One. 2015. Apr.
Schumak B, Klocke K, Borsche M, Kuepper J, Biswas A, Mack M, Hörauf A, Dunay IR
(See online at https://doi.org/10.1371/journal.pone.0124080) - Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes. Acta Neuropath. Comm. 2016 March
Möhle L, Israel N, Paarman K, Krohn M, Pietkiewicz S, Müller M, Lavrik I, Schott B, Schlüter D, Gundelfinger ED, Montag D, Seifert U, Pahnke J, Dunay IR
(See online at https://doi.org/10.1186/s40478-016-0293-8) - Ly6Chi monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis. Cell Reports, 2016 April
Möhle L, Mattei M, Heimesaat M, Bereswill M, Fischer M, Alutis M, Fischer A, Hambardzumyan D, Matzinger P, Dunay IR and Wolf S
(See online at https://doi.org/10.1016/j.celrep.2016.04.074)
