Trained immunity of alveolar macrophages requires metabolic rewiring and type 1 interferon signaling

Abstract

Environmental microbial triggers shape the development and functionality of the immune system. Alveolar macrophages (AMs), tissue-resident macrophages of the lungs, are in constant and direct contact with inhaled particles and microbes. Such exposures likely impact AM reactivity to subsequent challenges by immunological imprinting mechanisms referred to as trained immunity. Here, we investigated whether a ubiquitous microbial compound has the potential to induce AM training in vivo. We discovered that intranasal exposure to ambient amounts of lipopolysaccharide (LPS) induced a pronounced AM memory response, characterized by enhanced reactivity upon pneumococcal challenge. Exploring the mechanistic basis of AM training, we identified a critical role of type 1 interferon signaling and found that inhibition of fatty acid oxidation and glutaminolysis significantly attenuated the training effect. Notably, adoptive transfer of trained AMs resulted in increased bacterial loads and tissue damage upon subsequent pneumococcal infection. In contrast, intranasal pre-exposure to LPS promoted bacterial clearance, highlighting the complexity of stimulus-induced immune responses, which likely involve multiple cell types and may depend on the local immunological and metabolic environment. Collectively, our findings demonstrate the profound impact of ambient microbial exposure on pulmonary immune memory and reveal tissue-specific features of trained immunity.

Tissue-specific macrophages: how they develop and choreograph tissue biology

“…Moreover, the recognition of danger signals, such as lipopolysaccharide, has been linked to tissue adaptation via changes in the macrophage compartment. Here, lipopolysaccharide-induced low-grade inflammation triggered the recruitment and establishment of a long-lived MDM compartment with enhanced pro-inflammatory capabilities 144 . Pulmonary viral infections were also linked to a more efficient CD8 + T cell response, mediated by functional modification of alveolar macrophages post-viral infection 145 .…”

RIG-I activation primes and trains innate antiviral immune memory

“…However, Dectin-1 signaling is also known to induce type-I IFN through IRF5(del Fresno et al , 2013; Mata-Martínez et al , 2022) which may contribute to its training effects. Furthermore, a very recent study has also shown that type I IFN-signaling is essential for LPS mediated TI in alveolar macrophages(Zahalka et al , 2022). Thus, type I IFN signaling may even be a universal feature of TI and should be further investigated for stimuli such as the BCG vaccine.…”

Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation

“…Earlier studies have examined the development of monocyte-derived AMs during pathological insults, such as viral infections, radiation or bleomycin-induced fibrosis (Aegerter et al, 2020; Li et al, 2022a; Machiels et al, 2017; Misharin et al, 2017). However, how broncho-alveolar macrophages adapt their transcriptome, metabolism and function to ambient immune stimulatory components, such as LPS or β-glucan, after the acute or sub-acute recognition phase remains poorly understood (Zahalka et al, 2022). Here, we show that although the initial inflammation evoked by β-glucan is minimal, functionally modified monocyte-derived AMs arise from Ly6c + monocytes within the air-exposed space of the lung, a process affiliated to strong pathology-induction, as e.g.…”