Lung resident neutrophils need to be tightly regulated to avoid degranulation-and cytokine-associated damage to fragile alveolar structures that can lead to fatal outcomes. Here we show that lung neutrophils (LNs) express distinct surface proteins and genes that definitely distinguish LNs from bone marrow and blood neutrophils. Functionally, LNs show impaired migratory activity toward chemoattractants and produce high levels of IL-6 at steady state and low levels of TNF-α in response to LPS challenge. Treating bone marrow neutrophils with bronchoalveolar lavage fluid or prostaglandin E2 induces LN-associated characteristics including the expression of transglutaminase 2 (Tgm2) and reduced production of inflammatory cytokines upon LPS challenge. Neutrophils from Tgm2-/- mice release high levels of inflammatory cytokines in response to LPS. Lung damage is significantly exacerbated in Tgm2-/- mice in an LPS-induced acute respiratory distress syndrome model. Collectively, we demonstrate that prostaglandin E2 is a key factor for the generation of LNs with unique immune suppressive characteristics, acting through protein kinase A and Tgm2, and LNs play essential roles in the protection of the lungs against pathogenic inflammation.

Pseudomonas aeruginosa ( P. aeruginosa ) is a well-known Gram-negative opportunistic pathogen. Neutrophils play key roles in mediating host defense against P. aeruginosa infection. In this study, we identified a metabolite derived from P. aeruginosa that regulates neutrophil activities. Using gas chromatography-mass spectrometry, a markedly increased level of 2-undecanone was identified in the peritoneal fluid of P. aeruginosa -infected mice. 2-Undecanone elicited the activation of neutrophils in a G ai -phospholipase C pathway. However, 2-undecanone strongly inhibited responses to lipopolysaccharide and bactericidal activity of neutrophils against P. aeruginosa by inducing apoptosis. Our results demonstrate that 2-undecanone from P. aeruginosa limits the innate defense activity of neutrophils, suggesting that the production of inhibitory metabolites is a strategy of P. aeruginosa for escaping the host immune system.