IL-1-dependent enteric gliosis guides intestinal inflammation and dysmotility and modulates macrophage function

Abstract

Muscularis Externa Macrophages (ME-Macs) and enteric glial cells (EGCs) are closely associated cell types in the bowel wall, and important interactions are thought to occur between them during intestinal inflammation. They are involved in developing postoperative ileus (POI), an acute, surgery-induced inflammatory disorder triggered by IL-1 receptor type I (IL1R1)-signaling. In this study, we demonstrate that IL1R1-signaling in murine and human EGCs induces a reactive state, named enteric gliosis, characterized by a strong induction of distinct chemokines, cytokines, and the colony-stimulating factors 1 and 3. Ribosomal tagging revealed enteric gliosis as an early part of POI pathogenesis, and mice with an EGC-restricted IL1R1-deficiency failed to develop postoperative enteric gliosis, showed diminished immune cell infiltration, and were protected from POI. Furthermore, the IL1R1-deficiency in EGCs altered the surgery-induced glial activation state and reduced phagocytosis in macrophages, as well as their migration and accumulation around enteric ganglia. In patients, bowel surgery also induced IL-1-signaling, key molecules of enteric gliosis, and macrophage activation. Together, our data show that IL1R1-signaling triggers enteric gliosis, which results in ME-Mac activation and the development of POI. Intervention in this pathway might be a useful prophylactic strategy in preventing such motility disorders and gut inflammation.

BQ788 reveals glial ETB receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus

“…'Reactive' enteric glial cells are emerging as an important target of investigation in neurogastroenterology and motility for gastrointestinal diseases (Gulbransen & Christofi, 2018;Mazzotta et al, 2020;Ochoa-Cortes et al, 2016;Schneider et al, 2021Schneider et al, , 2022Stoffels et al, 2014). 'Reactive' glia are…”

“…The availability of more selective tools to study ET B receptor signalling, including selective drugs such as BQ788 or sarafotoxin, Tg (Ednrb-EGFP)EP59Gsat/Mmucd mice, specific antisera against EGFP, ET-1 and ET B receptor, cell-specific Ca 2+ reporter mice for glia (Sox10 CreERT2 ;GCaMP5g-tdT) or neurons (Wnt1 Cre2 ;GCaMP5g-tdT) to monitor enteric nervous system activation, RiboTag mice, and spatiotemporal imaging of peristalsis, provided definitive ways to investigate ET B receptor signalling in health or disease. To evaluate ET B receptor signalling in 'reactive' glia, we used an established mouse model of postoperative ileus (POI) that is linked to muscularis externa (ME) inflammation and disruption of motility (Schneider et al, 2021(Schneider et al, , 2022Stoffels et al, 2014). ET B receptor signalling in human enteric glia was confirmed by Ca 2+ imaging in glial networks obtained from surgical specimens.…”

“…signalling in 'reactive' glia (Bhave et al, 2017;Gulbransen et al, 2012;Liñán-Rico et al, 2016;McClain & Gulbransen, 2017;Schneider et al, 2021;Schneider et al, 2022;Stoffels et al, 2014) is altered after gut inflammation in a well characterized POI mouse model of muscularis externa inflammation induced by surgical intestinal manipulation (IM) (Schneider et al, 2021;Schneider et al, 2022;Stoffels et al, 2014) (Figures S7 and S8). In the POI model, inflammation (Figures S7 and S8) and disruption of motility (slower GI transit) are hallmarks of the disease.…”

Enteric Glial Cell Network Function is Required for Epithelial Barrier Restitution following Intestinal Ischemic Injury in the Early Postnatal Period

“…(68) In the gut, gliosis involves enhanced inflammatory signaling in EGC, and it has been reported increasingly in the literature in response to many intestinal disease and injury states like chemotherapy, inflammation, infection and motility disorders. (32,57,(69)(70)(71)(72) This reactive state is associated with the release of many cytokines and glial factors which would have direct interactions with the mucosal barrier, and…”

“…(68) In the gut, gliosis involves enhanced inflammatory signaling in EGC, and it has been reported increasingly in the literature in response to many intestinal disease and injury states like chemotherapy, inflammation, infection and motility disorders. (32,57,(69)(70)(71)(72) This reactive state is associated with the release of many cytokines and glial factors which would have direct interactions with the mucosal barrier, and thus could be an important component to mucosal response to acute injury as seen in this pig model of acute intestinal injury. In keeping with this, when treating injured EGC with glial cell inhibitor fluoroacetate (FA), ischemia-induced upregulation of GFAP, one described marker of the EGC gliosis phenotype, is inhibited.…”