Microbial energy metabolism fuels an intestinal macrophage niche in solitary isolated lymphoid tissues through purinergic signaling

Abstract

Maintaining macrophage (MΦ) heterogeneity is critical to ensure intestinal tissue homeostasis and host defense. The gut microbiota and host factors are thought to synergistically guide intestinal MΦ development, although the exact nature, regulation, and location of such collaboration remain unclear. Here, we report that microbial biochemical energy metabolism promotes colony-stimulating factor 2 (CSF2) production by group 3 innate lymphoid cells (ILC3s) within solitary isolated lymphoid tissues (SILTs) in a cell-extrinsic, NLRP3/P2X7R-dependent fashion in the steady state. Tissue-infiltrating monocytes accumulating around SILTs followed a spatially constrained, distinct developmental trajectory into SILT-associated MΦs (SAMs). CSF2 regulated the mitochondrial membrane potential and reactive oxygen species production of SAMs and contributed to the antimicrobial defense against enteric bacterial infections. Collectively, these findings identify SILTs and CSF2-producing ILC3s as a microanatomic niche for intestinal MΦ development and functional programming fueled by the integration of commensal microbial energy metabolism.

Extracellular ATP is an environmental cue in bacteria

“…Until recently, a contribution of eATP to host-microbe interactions was not appreciated. However, eATP is present in the nano- to micromolar range in culture supernatants (Atarashi et al , 2008) or homogenates (Chiaranunt et al , 2023) of murine faeces and many isolated bacteria (Abbasian et al ., 2019; Baeza & Mercade, 2021; Chiaranunt et al ., 2023; Ding Quah & Tan, 2016; Hironaka et al , 2013; Ihssen et al , 2021; Ivanova et al , 2006; Iwase et al , 2010; Mempin et al ., 2013; Nolan et al ., 2015; Qiu et al , 2019), during osmotic shock (Berrier et al , 1992), treatment with antimicrobial peptides (Alvarez et al , 2017; Valat et al , 2003) or antibiotics (Abbasian et al ., 2019; Ihssen et al ., 2021; Nilsson, 1978; Proietti et al , 2019; Yu Lomakina & Ugarova, 2022). During homeostasis, eATP is found in the gut lumen at low concentration (Kusu et al , 2013; Malo et al ., 2014; Patel, 2014; Perruzza et al , 2017; Proietti et al ., 2019; Puhar et al , 2013; Scott et al , 2021; Tani et al , 2021).…”

“…Rotavirus also initiates epithelial purinergic signalling (Chang-Graham et al , 2020). During Shiga toxin-producing enterohaemorrhagic Escherichia coli (Arvidsson et al , 2022) or Citrobacter rodentium infection (Chiaranunt et al ., 2023) and Tritrichomonas musculis colonisation (Chiaranunt et al , 2022) eATP is present in faeces. Helminths induce ATP release in the gut (Chen et al , 2022).…”

“…Bacteria are typically exposed to low concentrations of eATP, partly originating from themselves. In fact, eATP is present in the nano- to micromolar range in culture supernatants 21 or homogenates 22 of murine faeces and many isolated bacteria in culture 13,15,18,20,22–28 at steady state. Additionally, eATP is found in bacterial supernatants upon osmotic shock 29 , treatment with antimicrobial peptides 30,31 or antibiotics 18,28,32–34 , or compromised outer membrane stability 35 .…”

“…Rotavirus also initiates epithelial purinergic signalling 43 . During Shiga toxin-producing enterohaemorrhagic E. coli 44 or Citrobacter rodentium infection 22 and Tritrichomonas musculis colonisation 45 high eATP is present in faeces. Helminths induce ATP release in the gut 46 .…”