Lactate produced by alveolar type II cells suppresses inflammatory alveolar macrophages in acute lung injury

Abstract

Alveolar inflammation is a hallmark of acute lung injury (ALI), and its clinical correlate is acute respiratory distress syndrome—and it is as a result of interactions between alveolar type II cells (ATII) and alveolar macrophages (AM). In the setting of acute injury, the microenvironment of the intra‐alveolar space is determined in part by metabolites and cytokines and is known to shape the AM phenotype. In response to ALI, increased glycolysis is observed in AT II cells, mediated by the transcription factor hypoxia‐inducible factor (HIF) 1α, which has been shown to decrease inflammation. We hypothesized that in acute lung injury, lactate, the end product of glycolysis, produced by ATII cells shifts AMs toward an anti‐inflammatory phenotype, thus mitigating ALI. We found that local intratracheal delivery of lactate improved ALI in two different mouse models. Lactate shifted cytokine expression of murine AMs toward increased IL‐10, while decreasing IL‐1 and IL‐6 expression. Mice with ATII‐specific deletion of Hif1a and mice treated with an inhibitor of lactate dehydrogenase displayed exacerbated ALI and increased inflammation with decreased levels of lactate in the bronchoalveolar lavage fluid; however, all those parameters improved with intratracheal lactate. When exposed to LPS (to recapitulate an inflammatory stimulus as it occurs in ALI), human primary AMs co‐cultured with alveolar epithelial cells had reduced inflammatory responses. Taken together, these studies reveal an innate protective pathway, in which lactate produced by ATII cells shifts AMs toward an anti‐inflammatory phenotype and dampens excessive inflammation in ALI.

Absence of c-Maf and IL-10 enables Type I IFN enhancement of innate responses to low-dose LPS in alveolar macrophages

“…In this way, c-Maf mediates a trade-off in AMs between proliferative capacity and production of IL-10. While production of IL- 10 early during an infection response might be detrimental to mounting effective host immune responses 55,56 , IL-10 is critical during chronic disease and inflammation to prevent immunopathology, including under conditions such as Acute Lung Injury (ALI) 57 . Further investigation is needed into the potential in vivo and context-dependent impacts of AM IL-10 production.…”

Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury

“…Functional cell death caused by sustained hyper-lactate environments may worsen local hypoxia, promote lactate production, and lead to a vicious cycle of tissue damage in sepsis [ 37 ]. However, some studies have suggested that lactate can inhibit the release of inflammatory cytokines in macrophages during acute lung injury, indicating heterogeneity in its effects on different cells [ 38 ]. Recent research has found lactate to be a more efficient carbon source than glucose in the tricarboxylic acid cycle [ 39 ].…”