Abstract
Monocytes play key roles in the maintenance of homeostasis and in the control of the infection. Monocytes are recruited from the bone marrow to inflammatory sites and are essential for antimicrobial activity to limit tissue damage and promote adaptive T cell responses. Here, we investigated the role of Nuclear Factor of Activated T cells 1 (NFAT1) in the regulation of Ly6Chi inflammatory monocyte recruitment to the CNS upon T. gondii infection. We show that NFAT-1-deficient monocytes are unable to migrate to the CNS of T. gondii-infected mice. Moreover, NFAT1−/− mice are highly susceptible to chronic T. gondii infection due to a failure to control parasite replication in the CNS. The inhibition of Ly6Chi inflammatory monocyte recruitment to the CNS severely blocked CXCL10 production and consequently the migration of IFN-γ-producing CD4+ T cells. Moreover, the transfer of Ly6Chi monocytes to infected NFAT1−/− mice favored CD4+ T cell migration to the CNS and resulted in the inhibition of parasite replication and host defense. Together, these results demonstrated for the first time the contribution of NFAT1 to the regulation of Ly6Chi monocyte recruitment to the CNS and to resistance during chronic T. gondii infection.
Highlights
Monocytes are a subset of circulating white blood cells that can differentiate into tissue macrophages and dendritic cells in a CCR2-dependent manner [1]
In the absence of Nuclear factor of activated T cells (NFAT)-1, the inflammatory infiltrate in the central nervous system (CNS) was reduced compared to that of WT mice (Figures 1E,F). These data indicate that Nuclear Factor of Activated T cells 1 (NFAT1) contributes to the control of parasite replication in the CNS, suggesting that it is essential to the resistance to chronic infection by T. gondii
We found a reduction in the frequency and absolute numbers of Ly6Chi inflammatory monocytes gated on CD11b+CD45hi in the CNS from NFAT1−/− mice compared to WT mice (Figures 3A,B)
Summary
Monocytes are a subset of circulating white blood cells that can differentiate into tissue macrophages and dendritic cells in a CCR2-dependent manner [1]. During homeostasis and inflammation, circulating monocytes leave the bloodstream and migrate into tissues following stimulation with cytokines, chemokines, and/or microbial products [2]. Toxoplasmosis is a worldwide zoonotic infection caused by the opportunistic intracellular parasite Toxoplasma gondii [9]. The parasites invade the intestinal epithelium and induce a strong Th1-type immune response associated with the production of IL-12 by dendritic cells (DCs), macrophages, and neutrophils, which drives the production of IFNγ by T cells and NK cells, main mediator of acute defenses against the parasite [10]
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