Microglia, seen from the CX3CR1 angle

Abstract

Microglial cells in brain and spinal cord are characterized by high expression of the chemokine receptor CX3CR1. Expression of the sole CX3CR1 ligand, the membrane-tethered and sheddable chemokine CX3CL1/fractalkine, is restricted in the brain parenchyma to selected neurons. Here we summarize our current understanding of the physiological role of CX3CR1 for microglia function and the CX3C axis in microglial/neuronal crosstalk in homeostasis and under challenge. Moreover, we will discuss the efforts of our laboratory and others to exploit CX3CR1 promoter activity for the visualization and genetic manipulation of microglia to probe their functional contributions in the central nerve system (CNS) context.

Keywords: CX3CR1; Cre-loxP knock-in mice; microglia; neuroimmunology; neuropathology.

Figure 1

(A) Schematic of CX₃C chemokine family and (B) potential scenario of differential outcomes of neuronal shed and membrane-anchored CX₃CL1 engagement by microglia inducing or suppressing microglial IL-1β production, respectively.

Figure 2

Brain section of CX₃CR1^gfp:CX₃CL1^cherry double reporter animals (Kim et al., 2011) highlighting CX₃CR1-expressing microglia and subsets of CX₃CL1-expressing neurons in specific brain regions. Note that both reporters are expressed in the cytoplasm and not as fusion proteins. Thus they reflect the respective promoter activity but not the presence of the respective proteins. Hence no co-localization has to be expected.

Figure 3

(A) Schematic of modified CX₃CR1 loci of CX₃CR1^gfp mice (Jung et al., 2000) and (B) CX₃CR1^Cre and CX₃CR1^CreER mice (Yona et al., 2013); (C) Efficient YFP labeling of both spinal cord and brain microglia in CX₃CR1^CreER and CX₃CR1^Cre mice crossed with R26-YFP reporter mice. CX₃CR1^CreER:R26-YFP mice were treated with tamoxifen to induce the rearrangement (Yona et al., 2013); (D) Induction but subsequent progressive loss of cells harboring gene rearrangements in peripheral myeloid cells (monocytes, intestinal macrophages) and persistence of genomic modification in microglial cells.