Lung immune tone via gut-lung axis: gut-derived LPS and short-chain fatty acids’ immunometabolic regulation of lung IL-1β, FFAR2, and FFAR3 expression
Abstract
Microbial metabolites produced by the gut microbiome, e.g. short-chain fatty acids (SCFA), have been found to influence lung physiology and injury responses. However, how lung immune activity is regulated by SCFA is unknown. We examined fresh human lung tissue and observed the presence of SCFA with interindividual variability. In vitro, SCFA were capable of modifying the metabolic programming in LPS-exposed alveolar macrophages (AM). We hypothesized that lung immune tone could be defined by baseline detection of lung intracellular IL-1β. Therefore, we interrogated naïve mouse lungs with intact gut microbiota for IL-1β mRNA expression and localized its presence within alveolar spaces, specifically within AM subsets. We established that metabolically active gut microbiota, which produce SCFA, can transmit LPS and SCFA to the lung and thereby could create primed lung immunometabolic tone. To understand how murine lung cells sensed and upregulated IL-1β in response to gut microbiome-derived factors, we determined that, in vitro, AM and alveolar type II (AT2) cells expressed SCFA receptors, free fatty acid receptor 2 (FFAR2), free fatty acid receptor 3 (FFAR3), and IL-1β but with distinct expression patterns and different responses to LPS. Finally, we observed that IL-1β, FFAR2, and FFAR3 were expressed in isolated human AM and AT2 cells ex vivo, but in fresh human lung sections in situ, only AM expressed IL-1β at rest and after LPS challenge. Together, this translational study using mouse and human lung tissue and cells point to an important role for the gut microbiome and their SCFA in establishing and regulating lung immune tone.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 01, 2021
- Source ID
- 10.1152/ajplung.00421.2020
Entities
People
- Arun Prakash
- Daisuke Maruyama
- Mehrdad Arjomandi
- Qing Liu
- Xiaoli Tian
Organizations
- Capital Medical University
- FAMRI
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- San Francisco General Hospital
- United States Department of Defense
- United States Department of Veterans Affairs
- University of California, San Francisco
- Veterans Health Administration