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. 2015 Oct 8;9:403.
doi: 10.3389/fncel.2015.00403. eCollection 2015.

Neuron-macrophage Crosstalk in the Intestine: A "Microglia" Perspective

Free PMC article

Neuron-macrophage Crosstalk in the Intestine: A "Microglia" Perspective

Simon Verheijden et al. Front Cell Neurosci. .
Free PMC article


Intestinal macrophages are strategically located in different layers of the intestine, including the mucosa, submucosa and muscularis externa, where they perform complex tasks to maintain intestinal homeostasis. As the gastrointestinal tract is continuously challenged by foreign antigens, macrophage activation should be tightly controlled to prevent chronic inflammation and tissue damage. Unraveling the precise cellular and molecular mechanisms underlying the tissue-specific control of macrophage activation is crucial to get more insight into intestinal immune regulation. Two recent reports provide unanticipated evidence that the enteric nervous system (ENS) acts as a critical regulator of macrophage function in the myenteric plexus. Both studies clearly illustrate that enteric neurons reciprocally interact with intestinal macrophages and are actively involved in shaping their phenotype. This concept has striking parallels with the central nervous system (CNS), where neuronal signals maintain microglia, the resident macrophages of the CNS, in a quiescent, anti-inflammatory state. This inevitably evokes the perception that the ENS and CNS share mechanisms of neuroimmune interaction. In line, intestinal macrophages, both in the muscularis externa and (sub)mucosa, express high levels of CX3CR1, a feature that was once believed to be unique for microglia. CX3CR1 is the sole receptor of fractalkine (CX3CL1), a factor mainly produced by neurons in the CNS to facilitate neuron-microglia communication. The striking parallels between resident macrophages of the brain and intestine might provide a promising new line of thought to get more insight into cellular and molecular mechanisms controlling macrophage activation in the gut.

Keywords: CX3CR1; enteric nervous system; intestinal macrophage; microglia; neuroimmune; transforming growth factor β.


Figure 1
Figure 1
Expression of microglia specific genes in different macrophage subsets. (A) Box-and-whiskers plot of the means-normalized expression values of “microglia specific genes” C3ar1, Hpgds, Stab1, Ccr5, Olfml3, Cx3cr1, Tgfbr1, Entpd1, Ccl12 and Gas6 in different macrophage subsets. (B) Box-and-whiskers plot of the means-normalized expression values of “microglia specific transcription factors” Egr1, Atf3 and Junb in different macrophage subsets. List of microglia specific genes is based on Butovsky et al. (2014); Gene expression of different macrophage subsets is based on publically available microarray data from Immunological genome consortium (ImmGen; Heng and Painter, 2008). Plots were obtained through the “My GeneSet databrowser” on the Immgen site. Long red horizontal line represents the mean expression of all values in the graph. Black dots are expression values of single genes relative to the mean expression. Gray boxes are box-and-whiskers plots with short red lines representing the median expression value within a macrophage subset.

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