IL-33-Mediated Protection against Experimental Cerebral Malaria Is Linked to Induction of Type 2 Innate Lymphoid Cells, M2 Macrophages and Regulatory T Cells

Abstract

Cerebral malaria (CM) is a complex parasitic disease caused by Plasmodium sp. Failure to establish an appropriate balance between pro- and anti-inflammatory immune responses is believed to contribute to the development of cerebral pathology. Using the blood-stage PbA (Plasmodium berghei ANKA) model of infection, we show here that administration of the pro-Th2 cytokine, IL-33, prevents the development of experimental cerebral malaria (ECM) in C57BL/6 mice and reduces the production of inflammatory mediators IFN-γ, IL-12 and TNF-α. IL-33 drives the expansion of type-2 innate lymphoid cells (ILC2) that produce Type-2 cytokines (IL-4, IL-5 and IL-13), leading to the polarization of the anti-inflammatory M2 macrophages, which in turn expand Foxp3 regulatory T cells (Tregs). PbA-infected mice adoptively transferred with ILC2 have elevated frequency of M2 and Tregs and are protected from ECM. Importantly, IL-33-treated mice deleted of Tregs (DEREG mice) are no longer able to resist ECM. Our data therefore provide evidence that IL-33 can prevent the development of ECM by orchestrating a protective immune response via ILC2, M2 macrophages and Tregs.

Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism

“…In contrast, we found that CD11b ϩ cells markedly expanded in the spleen, and higher proportions of these cells were determined in brain infiltrates of infected Cnr2 Ϫ/Ϫ mice. Our findings suggest that increased numbers of CD11b ϩ CD11b ϩ cells has recently been described as a macrophage subset that accumulated after IL-33 treatment in the spleens of PbA-infected C57BL/6 mice and mediated resistance to CM due to anti-inflammatory properties (45). However, CD11b has also been described on subsets of adaptive immune cells among those CD8 ϩ T cells (46).…”

Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation

“…In vitro , IL-33 promotes proliferation of ST2 + Tregs and further enhances GATA3 expression, which stabilizes FoxP3 expression while increasing ST2 expression in a feed-forward reinforcing manner (Schiering et al, 2014; Vasanthakumar et al, 2015). Although IL-33 has direct effects on Treg stabilization and function, IL-33 also promotes ILC2 and/or dendritic cell subsets that enhance Treg numbers and function by indirect mechanisms (Besnard et al, 2015; Duan et al, 2012; Matta et al, 2014; Molofsky et al, 2015). Tregs generated during the perinatal period express ST2 and are highly suppressive and proliferative (Yang et al, 2015).…”

“…Similarly, mice lacking the IL-1β receptor, IL-1R, or the adaptor MyD88, had more robust intestinal granuloma formation when infected with Heligmosomoides polygyrus (Reynolds et al, 2014). In models of cerebral malaria, IL-33 administration protected against Th1 cell-associated lethality by inducing ILC2s and Tregs (Besnard et al, 2015). IFN-γ potently inhibits IL-33-mediated ILC2 activation in vitro and in vivo following Listeria infection (Molofsky et al, 2015).…”

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

“…90 Similar to Th2 cells, ILC2 could also respond to epithelium-derived IL-33 and facilitate AAM polarization by producing IL-13 and IL-5. 91 …”