Myeloid-epithelial cross talk coordinates synthesis of the tissue-protective cytokine leukemia inhibitory factor during pneumonia

• Published in: American journal of physiology. Lung cellular and molecular physiology 2017-09, Vol.313 (3), p.L548-L558
• Main Authors: Traber, Katrina E, Symer, Elise M, Allen, Eri, Kim, Yuri, Hilliard, Kristie L, Wasserman, Gregory A, Stewart, Colin L, Jones, Matthew R, Mizgerd, Joseph P, Quinton, Lee J
• Format: Article
• Language: English
• Subjects: Alveolar Epithelial Cells - metabolism; Alveolar Epithelial Cells - pathology; Animals; Bone marrow; Bronchoalveolar Lavage Fluid; Bronchus; Cell injury; Cell Line; Cellular manufacture; Chimeras; Complications; Crosstalk; Cytokines; Epithelial cells; Epithelial Cells - metabolism; Epithelium; Escherichia coli - physiology; Female; Hematopoiesis; Interleukin 6; Leukemia; Leukemia inhibitory factor; Leukemia Inhibitory Factor - biosynthesis; Leukemia Inhibitory Factor - genetics; Lung - metabolism; Lung - pathology; Lungs; Macrophages, Alveolar - metabolism; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mutation; Myeloid cells; Myeloid Cells - metabolism; NF-κB protein; Pneumonia; Pneumonia, Bacterial - metabolism; Pneumonia, Bacterial - microbiology; Pneumonia, Bacterial - pathology; Respiratory distress syndrome; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Signaling; Tissues; Transcription; Transcription Factor RelA - metabolism
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00482.2016

In bacterial pneumonia, lung damage resulting from epithelial cell injury is a major contributor to the severity of disease and, in some cases, can lead to long-term sequelae, especially in the setting of severe lung injury or acute respiratory distress syndrome. Leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, is a critical determinant of lung tissue protection during pneumonia, but the cellular sources of LIF and the signaling pathways leading to its production in the infected lung are not known. Here, we demonstrate that lung epithelium, specifically alveolar type II cells, is the predominant site of LIF transcript induction in pneumonic mouse lungs. Epithelial cell cultures were induced to express LIF by bacteria and by sterile bronchoalveolar lavage fluid from pneumonic mice. Reciprocal bone marrow chimera studies demonstrated that LIF deficiency in the nonhematopoietic compartment, but not LIF deficiency in hematopoietic cells, eliminated LIF induction during pneumonia. Although NF-κB RelA (p65) is essential for the expression of many cytokines during pneumonia, its targeted mutation in the lung epithelium was inconsequential for pneumonia-driven LIF induction. However, maximal expression of this epithelial-derived cytokine was dependent on NF-κB RelA in myeloid cells. Overall, our data suggest a signaling axis whereby activation of NF-κB RelA in myeloid cells promotes epithelial LIF induction during lung infections, representing a means through which these two cell types collaborate to improve tissue resilience during pneumonia.