Proline metabolism reprogramming of trained macrophages induced by early respiratory infection combined with allergen sensitization contributes to development of allergic asthma in childhood of mice

Abstract

BackgroundInfants with respiratory syncytial virus (RSV)-associated bronchiolitis are at increased risk of childhood asthma. Recent studies demonstrated that certain infections induce innate immune memory (also termed trained immunity), especially in macrophages, to respond more strongly to future stimuli with broad specificity, involving in human inflammatory diseases. Metabolic reprogramming increases the capacity of the innate immune cells to respond to a secondary stimulation, is a crucial step for the induction of trained immunity. We hypothesize that specific metabolic reprogramming of lung trained macrophages induced by neonatal respiratory infection is crucial for childhood allergic asthma.ObjectiveTo address the role of metabolic reprogramming in lung trained macrophages induced by respiratory virus infection in allergic asthma.MethodsNeonatal mice were infected and sensitized by the natural rodent pathogen Pneumonia virus of mice (PVM), a mouse equivalent strain of human RSV, combined with ovalbumin (OVA). Lung CD11b+ macrophages in the memory phase were re-stimulated to investigate trained immunity and metabonomics. Adoptive transfer, metabolic inhibitor and restore experiments were used to explore the role of specific metabolic reprogramming in childhood allergic asthma.ResultsPVM infection combined with OVA sensitization in neonatal mice resulted in non-Th2 (Th1/Th17) type allergic asthma following OVA challenge in childhood of mice. Lung CD11b+ macrophages in the memory phage increased, and showed enhanced inflammatory responses following re-stimulation, suggesting trained macrophages. Adoptive transfer of the trained macrophages mediated the allergic asthma in childhood. The trained macrophages showed metabolic reprogramming after re-stimulation. Notably, proline biosynthesis remarkably increased. Inhibition of proline biosynthesis suppressed the development of the trained macrophages as well as the Th1/Th17 type allergic asthma, while supplement of proline recovered the trained macrophages as well as the allergic asthma.ConclusionProline metabolism reprogramming of trained macrophages induced by early respiratory infection combined with allergen sensitization contributes to development of allergic asthma in childhood. Proline metabolism could be a well target for prevention of allergic asthma in childhood.

Hypercapnia alters mitochondrial gene expression and acylcarnitine production in monocytes

“…Proline is an important structural amino acid linked with collagen deposition and also has roles as an antioxidant and in immune responses 41 . Proline metabolism is also linked to the development of “trained” macrophages that predispose to allergic asthma 42 . The full consequence of reduced proline levels in monocytes exposed to hypercapnia remains to be elucidated, but may be relevant in wound healing and in determining immune cell phenotype.…”

“…41 Proline metabolism is also linked to the development of "trained" macrophages that predispose to allergic asthma. 42 The full consequence of reduced proline levels in monocytes exposed to hypercapnia remains to be elucidated, but may be relevant in wound healing and in determining immune cell phenotype. Our data relating to PYCR1 and proline, in addition to our data relating to ACADs and acylcarnitine, clearly suggest a coordinated transcriptomic and metabolomic response to acute hypercapnia under pH-buffered conditions.…”

The causes and consequences of trained immunity in myeloid cells

“…Neonatal mice infected with Pneumonia virus of mice (PVM, which is pathogenically similar to the respiratory syncytial virus [RSV] that affects humans) and stimulated with ovalbumin, have established trained immunity with increased Pro biosynthesis in alveolar macrophages ( 125 ). In addition, Asp was shown to be highly induced in trained macrophages compared to non-trained cells.…”