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

René M. Roy, Ayed Allawzi, Nana Burns, Christina Sul, Victoria Rubio, Jessica Graham, Kurt Stenmark, Eva S. Nozik, Rubin M. Tuder, Christine U. Vohwinkel

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article numbere23316
JournalFASEB Journal
Volume37
Issue number12
DOIs
StatePublished - Dec 2023

Keywords

  • acute lung injury
  • acute respiratory distress syndrome
  • alveolar epithelium
  • alveolar macrophage
  • glycolysis
  • hypoxia-inducible factor
  • lactate

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