Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

Abstract

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.

Consecutive BNT162b2 mRNA vaccination induces short-term epigenetic memory in innate immune cells

“…Indeed, impaired type I IFN responses ( 23 ) and preexisting autoantibodies against type I IFN ( 44 , 45 ) have been shown to be associated with the severity of COVID-19. On the other hand, it has also been reported that hypoxemia complicated with ARDS causes monocytopenia and suppression of type I IFN signaling in mice ( 46 ) and that SARS-CoV-2 ORF6 ( 47 ) and nucleocapsid proteins ( 48 ) suppress type I IFN signaling in vitro. These conflicting reports suggest that the lower type I IFN responses to SARS-CoV-2 may be both a cause and a consequence of severe COVID-19.…”

NRF2 Activation Reprograms Defects in Oxidative Metabolism to Restore Macrophage Function in Chronic Obstructive Pulmonary Disease

“…This leads us to postulate that there is both central (bone marrow) reprogramming of newly formed monocytes which contribute to replenishment of the alveolar macrophage compartment in the diseased lung and peripheral (lung tissue) reprogramming of the alveolar macrophage compartment following exposure to the local inflammatory milieu and metabolic intermediaries. This concept is supported by emerging evidence that reprogramming of myelopoiesis has consequence for myeloid cell tissue effector functions in acute 45 and chronic inflammatory disease states 6,24 , with overlapping transcriptional signatures previously reported in COPD MDM and AM populations 46 and evidence of changes in DNA accessibility and methylation marks in the AM compartment during trained immune responses 47,48 .Metabolic plasticity is a crucial feature of macrophage adaptability, with the capacity to generate ATP via multiple metabolic pathways, namely glycolysis, oxidative phosphorylation and fatty acid oxidation 25,28 . Recent evidence has demonstrated that the dichotomy of glycolysis supporting acute inflammatory responses and oxidative metabolism fuelling sustained energy production is as an over simplification of macrophage bioenergetics, with significant cross talk required between these metabolic pathways 49,50,51 .…”

Immunometabolic Signature during Respiratory Viral Infection: A Potential Target for Host-Directed Therapies

“…The inflammatory microenvironment may induce metabolic reprogramming of neutrophils associated with severe outcomes of respiratory virus diseases [ 184 , 204 , 205 , 206 , 207 , 208 ]. The respiratory syncytial virus is associated with the production by neutrophils of oxygen radicals through arachidonic acid metabolism responsible for tissue damage and bronchoconstriction during pathogenesis [ 209 , 210 ].…”