Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages

Abstract

Summary Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to β2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations.

Immunologic impact of the intestine in metabolic disease

“…Consistently, activation of PI3K in insulin-expressing brain neurons triggers a cholinergic, antiinflammatory reflex to limit inflammation in the fat (96), and a brain/liver axis mediates the ability of resistin to stimulate the expression of hepatic inflammatory molecules (97). Furthermore, a neuronal reflex within the gut that regulates intestinal macrophages in response to bacterial infection was recently documented (98). These findings indicate that the brain regulates whole-body metabolic and immunologic homeostasis and suggest that disruption of the gut/brain axis could lead to inflammation and glucose dysregulation in diabetes and obesity (Figure 2).…”

Molecular and Functional Neuroscience in Immunity

“…These specific catecholaminergic regulatory effects may be essential to controlling inflammatory responses (77, 78). Another recent study in mice provided important information about the functional inflammatory programming of macrophages in the gut wall and its neural catecholaminergic control (79). Macrophages localized in the lamina propria, underlying the epithelium, have a proinflammatory programming that is related to their active role in responding to damage in the epithelium (79).…”

“…Another recent study in mice provided important information about the functional inflammatory programming of macrophages in the gut wall and its neural catecholaminergic control (79). Macrophages localized in the lamina propria, underlying the epithelium, have a proinflammatory programming that is related to their active role in responding to damage in the epithelium (79). In contrast, muscularis macrophages deeper in the gut wall have a predominantly anti-inflammatory profile that is enhanced by the presence of pathogen ( Salmonella ) in the bowel (79).…”

“…Macrophages localized in the lamina propria, underlying the epithelium, have a proinflammatory programming that is related to their active role in responding to damage in the epithelium (79). In contrast, muscularis macrophages deeper in the gut wall have a predominantly anti-inflammatory profile that is enhanced by the presence of pathogen ( Salmonella ) in the bowel (79). Catecholaminergic neurons are a major source of regulatory signals for this enhancement, via β2-adrenergic receptors expressed on muscularis macrophages (79).…”

Janus-like monocytes regulate postoperative ileus

“…However macrophages are also present between the longitudinal and circular muscle layers of the ME, where they are in close proximity to the myenteric plexus 5 6. Recent studies indicate that LP and ME macrophages are phenotypically and functionally distinct under steady-state conditions 6. In particular, ME macrophages appear to have specialised tissue protection functions, including the production of factors such as bone morphogenic protein-2 (BMP2) that promote neuronal growth.…”