Abstract
Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage-TNF-IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers.
Highlights
The mucosal immune system maintains host–microbiota ho- coordinators of intestinal homeostasis
TLR4+ radiosensitive cells induce Intestinal epithelial cell (IEC) NF-κB activation upon LPS exposure To analyze NF-κB signaling dynamics in the gut mucosa, we used p65GFP-FL mice, where the p65 gene is replaced by a gene encoding a fusion protein of the NF-κB transcription factor p65 and GFP (De Lorenzi et al, 2009)
We concluded that the residual epithelial NF-κB activation observed in the p65GFP-FLxTlr4−/− > p65GFP-FL BMCs likely stemmed from residual radioresistant TLR4-proficient immune cells remaining in the recipients
Summary
The mucosal immune system maintains host–microbiota ho- coordinators of intestinal homeostasis. Their high phagocytic meostasis and defends against pathogen infections This is a activity and involvement in pathogen defense, inflammation, challenging task, as symbionts and pathogens share common and tissue repair place them at the nexus of this crosstalk microbe-associated molecular patterns, which are recognized by (Arnold et al, 2016; Bain and Schridde, 2018; Bernshtein et al, pattern recognition receptors (PRRs; Hausmann and Hardt, 2019; Chikina et al, 2020; Corbin et al, 2020; Joeris et al, 2017; 2019). Gene expression analysis Tissue RNA extraction (Hausmann et al, 2020a), organoid RNA extraction (Hausmann et al, 2020b), and qPCR analysis of the respective genes were performed as previously described (Hausmann et al, 2020a).
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