Activation of Invariant NKT Cells in Early Phase of Experimental Autoimmune Encephalomyelitis Results in Differentiation of Ly6Chi Inflammatory Monocyte to M2 Macrophages and Improved Outcome

Abstract

Neuropathology in multiple sclerosis is closely linked to presence of macrophages in the CNS. Both M1 (inflammatory) and M2 (alternatively activated, noninflammatory) macrophages are found in the inflamed CNS and thought to differentiate from infiltrating monocytes. It is unclear whether the balance of M1 and M2 macrophages can be altered and whether this affects disease outcome. We show in this article that Ly6Chi inflammatory monocytes are the early and dominant infiltrating cells in the CNS during experimental autoimmune encephalomyelitis, a model for the acute phase of multiple sclerosis. Activation of invariant NKT (iNKT) cells reduced the frequency of Ly6Chi monocytes and increased the proportion of M2 macrophages in the CNS with associated improvement in neurologic impairment. In contrast, iNKT-deficient mice showed higher numbers of Ly6Chi monocytes, reduced M2, and much more severe disease. Adoptive transfer of M2-enriched cells to iNKT-deficient mice markedly improved neurologic impairment. In vitro and in vivo experiments showed that iNKT cells promote differentiation of monocytes to M2 macrophages in an IL-4 and CD1d-dependent process. These findings indicate that infiltrating Ly6Chi inflammatory monocytes are early players in acute neuroinflammation and that their frequency and differentiation can be influenced by activation of iNKT cells with resultant improvement in disease outcome.

Cross-talk between iNKT cells and monocytes triggers an atheroprotective immune response in SLE patients with asymptomatic plaque

“…SLE-P serum was able to induce M2-like macrophage polarization but only in the presence of iNKT cells. This finding corroborates previous observations in experimental autoimmune encephalomyelitis, where iNKT cell deficient mice have fewer M2 macrophages and worse disease (43). Similarly, in a mouse model of obesity α-GalCer treatment significantly increased both iNKT cell numbers and M2 macrophage polarisation mediated by in part by IL-4 (44).…”

IL-10–producing NKT10 cells are a distinct regulatory invariant NKT cell subset

“…In regard to the αGalCer-induced EAE protection, however, is is not entirely clear which iNKT cellderived cytokine is important. IL-4 and/or IL-10 have been suggested (44,45,48,(64)(65)(66), but some data contradict this (46,61 However, based on our data, we propose that the protection against EAE by repetitive αGalCer challenge depends on the requirement to first induce sufficient numbers of NKT10 cells and then to subsequently stimulate IL-10 production from them. The generation of cells with an NKT10 cell phenotype in this model does not require their ability to produce IL-10, but we noticed a worsening of disease in mice that received IL-10-deficient iNKT cells compared with the control Jα18 -/-mice ( Figure 8B).…”

Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression

“…Another possibility is suggested by the finding that during acute allergic skin inflammation, basophils are a source of the IL-4 that polarizes newly recruited Ly6C hi monocytes to M2 macrophages (28). Furthermore, eosinophils have been identified as a source of IL-4/IL-13 for M2 macrophage polarization in adipose tissue under steady-state conditions and during acute helminth infection, and invariant NKT (iNKT) cells provide IL-4 to promote monocyte differentiation to M2 macrophages in experimental autoimmune encephalomyelitis (EAE) (41). Which of these immune cell subtypes is important for M2 polarization signaling in atherosclerosis regression is being actively investigated by our laboratory.…”