Enteric glial cells favor accumulation of anti-inflammatory macrophages during the resolution of muscularis inflammation

Abstract

Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective Mφs. Results showed that muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c+ monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mφ subpopulations during the resolution of muscularis inflammation, i.e. Cd206+ MhcIIhi and Timp2+ MhcIIlo Mφs. Interestingly, we found that damage to the micro-environment upon muscularis inflammation resulted in EGC activation, which in turn stimulated monocyte infiltration and the consequent differentiation in anti-inflammatory CD206+ Mφs via CCL2 and CSF1, respectively. In addition, CSF1-CSF1R signaling was shown to be essential for the differentiation of monocytes into CD206+ Mφs and EGC proliferation during muscularis inflammation. Our study provides a comprehensive insight into pro-resolving Mφ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mφs, thereby highlighting pro-resolving Mφ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.

IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer

“…Considering that the tumor monocyte population decreased upon EGC depletion, we speculate that CRC EGC-derived chemokines (i.e., CCL2 and CXCL5) could also promote the infiltration of monocytes in the colonic tumor site. This would be in line with our recent findings showing early expression of CCL2 by reactive EGCs in the context of intestinal inflammation (Stakenborg et al, 2022). However, further research will need to determine whether the pro-tumorigenic role of EGCs is exerted solely on the SPP1 + TAMs or whether EGCs also affect other immune or stromal cells via glial-derived factors.…”

“…Given the evidence that EGCs modulate their functions based on microenvironmental cues (Progatzky et al, 2021; Stakenborg et al, 2022; Schneider et al, 2021), we aimed at defining the factors driving the EGC phenotypic switch in CRC. Considering the heavy infiltration of the colon TME by immune cells, which recent studies have pinpointed as sources of EGC-activating factors (Progatzky et al, 2021), we investigated the possibility of immune cells driving CRC EGC transition, potentially creating a reinforcing neuroimmune feedback loop.…”

“…As it is well described that EGCs can adapt their functions according to microenvironmental cues 12,15,23 , we aimed at understanding which TME-derived factors could propagate the CRC EGC phenotypic switch. Therefore, considering that colon TME is highly infiltrated by immune cells which have been recently identified as providers of EGC activating factors 12 , we questioned if these cells were able to promote this process, thereby generating a positive neuroimmune feedback loop.…”

“…Of particular interest is their significant role in modulating immune responses in various intestinal diseases [11][12][13][14] . In this regard, we recently demonstrated that EGCs significantly affect macrophage recruitment and differentiation in a murine model of acute intestinal inflammation such as post-operative ileus 15,16 .…”

“…Upon activation during intestinal pathologies, EGCs contribute to the shaping of the inflammatory milieu through the secretion of a plethora of cytokines and chemokines (Schneider et al, 2021; Brown et al, 2016; Schneider et al, 2022; Rosenbaum et al, 2016). In this regard, we recently demonstrated the profound influence EGCs exert on macrophage dynamics in the setting of acute intestinal inflammation, promoting the recruitment of monocytes and their differentiation into pro-resolving macrophages (Stakenborg et al, 2022; Schneider et al, 2022).…”