Heterogeneity and tissue imprinting of intestinal resident macrophages revisited: from transcriptome to function

Intestinal macrophages are essential components of the gastrointestinal tract and exhibit highly specific functions depending on their anatomical location within the gut. Lamina propria macrophages face the gut lumen and are involved in bacterial clearance, initiation of adaptive immunity and installing oral tolerance. In contract, macrophages residing in the muscularis externa regulate intestinal peristaltic activity through direct crosstalk with enteric neurons. Increasing evidence from our group and others indeed suggests that the enteric nervous system (ENS) provides signals that account for the gut-specific macrophage phenotype. This tolerogenic transcriptome is characterized by an immunological quiescent state and linked to the prominent expression of the chemokine receptor CX3CR1 and other unique signature genes.

However, the mediator(s) released by the enteric neurons determining the tolerogenic phenotype are unexplored. Moreover, revealing this neuro-modulated macrophage population has been complicated by the heterogeneity of hematopoietic cells within the gastrointestinal tract. This dissertation is focused on the comprehensive characterization of the intestinal macrophage population involved in the communication with enteric neurons. ENS-derived signals that shape macrophage identity will be explored and we will investigate how the macrophage-enteric neuronal crosstalk reflects in both physiological (such as intestinal motility) and disease contexts (such as DSS colitis and post-operative ileus).