Enteric cross-talk

Intestinal epithelial barrier function is compromised in inflammatory bowel disease and barrier dysfunction contributes to disease progression. Extracellular nucleotides/nucleosides generated in gut inflammation may regulate barrier function through actions on diverse cell types. Enteric glia modulate extracellular purinergic signaling and exert pathophysiological effects on mucosal permeability. These glia may regulate inflammation with paracrine responses, theoretically mediated via adenosine 2B receptor (A_2BR) signaling. As the cell-specific roles of A_2BRs in models of colitis and barrier dysfunction are unclear, we studied glial A_2BRs in acute dextran sodium sulfate (DSS) colitis. We performed and validated conditional ablation of glial A_2BRs in Sox10^CreERT2+/−;Adora2b^f/f mice. Overt intestinal disease activity indices in DSS-colitis were comparable between Sox10^CreERT2+/–;Adora2b^f/f mice and littermate controls. However, ablating glial A_2BRs protected against barrier dysfunction following acute DSS-colitis. These benefits were associated with the normalization of tight junction protein expression and localization including claudin-1, claudin-8, and occludin. Glial A_2BR signaling increased levels of proinflammatory mediators in the colon and cell-intrinsic regulation of genes including Csf3, Cxcl1, Cxcl10, and Il6. Our studies show that glial A_2BR signaling exacerbates immune responses during DSS-colitis and that this adenosinergic cell-specific mechanism contributes to persistent gut epithelial barrier dysfunction.

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⁺ MhcII^hi and Timp2⁺ MhcII^lo 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.

The eye is a sensory organ exposed to the environment and protected by a mucosal tissue barrier. While it shares a number of features with other mucosal tissues, the ocular mucosal system, composed of the conjunctiva, Meibomian glands, and lacrimal glands, is specialized to address the unique needs of (a) lubrication and (b) host defense of the ocular surface. Not surprisingly, most challenges, physical and immunological, to the homeostasis of the eye fall into those two categories. Dry eye, a dysfunction of the lacrimal glands and/or Meibomian glands, which can both cause, or arise from, sensory defects, including those caused by corneal herpes virus infection, serve as examples of these perturbations and will be discussed ahead. To preserve vision, dense neuronal and immune networks sense various stimuli and orchestrate responses, which must be tightly controlled to provide protection, while simultaneously minimizing collateral damage. All this happens against the backdrop of, and can be modified by, the microorganisms that colonize the ocular mucosa long term, or that are simply transient passengers introduced from the environment. This review will attempt to synthesize the existing knowledge and develop trends in the study of the unique mucosal and immune elements of the ocular surface.