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Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.

ABSTRACT: Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.

SUBMITTER: Misharin AV

PROVIDER: S-EPMC5551573 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.

Misharin Alexander V AV Morales-Nebreda Luisa L Reyfman Paul A PA Cuda Carla M CM Walter James M JM McQuattie-Pimentel Alexandra C AC Chen Ching-I CI Anekalla Kishore R KR Joshi Nikita N Williams Kinola J N KJN Abdala-Valencia Hiam H Yacoub Tyrone J TJ Chi Monica M Chiu Stephen S Gonzalez-Gonzalez Francisco J FJ Gates Khalilah K Lam Anna P AP Nicholson Trevor T TT Homan Philip J PJ Soberanes Saul S Dominguez Salina S Morgan Vince K VK Saber Rana R Shaffer Alexander A Hinchcliff Monique M Marshall Stacy A SA Bharat Ankit A Berdnikovs Sergejs S Bhorade Sangeeta M SM Bartom Elizabeth T ET Morimoto Richard I RI Balch William E WE Sznajder Jacob I JI Chandel Navdeep S NS Mutlu Gökhan M GM Jain Manu M Gottardi Cara J CJ Singer Benjamin D BD Ridge Karen M KM Bagheri Neda N Shilatifard Ali A Budinger G R Scott GRS Perlman Harris H

The Journal of experimental medicine 20170710 8

Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course o ...[more]

PMID: 28694385

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Project description:Human alveolar macrophages (HAM) are primary bacterial niche and immune response cells during Mycobacterium tuberculosis (M.tb) infection, and human blood monocyte-derived macrophages (MDM) are a model for investigating M.tb-macrophage interactions. Here, we use a targeted RNA-Seq method to measure transcriptome-wide changes in RNA expression patterns of freshly obtained HAM (used within 6 h) and 6 day cultured MDM upon M.tb infection over time (2, 24 and 72 h), in both uninfected and infected cells from three donors each. The Ion AmpliSeq™ Transcriptome Human Gene Expression Kit (AmpliSeq) uses primers targeting 18,574 mRNAs and 2,228 non-coding RNAs (ncRNAs) for a total of 20,802 transcripts. AmpliSeqTM yields highly precise and reproducible gene expression profiles (R2 >0.99). Taking advantage of AmpliSeq's reproducibility, we establish well-defined quantitative RNA expression patterns of HAM versus MDM, including significant M.tb-inducible genes, in networks and pathways that differ in part between MDM and HAM. A similar number of expressed genes are detected at all time-points between uninfected MDM and HAM, in common pathways including inflammatory and immune functions, but canonical pathway differences also exist. In particular, at 2 h, multiple genes relevant to the immune response are preferentially expressed in either uninfected HAM or MDM, while the HAM RNA profiles approximate MDM profiles over time in culture, highlighting the unique RNA expression profile of freshly obtained HAM. MDM demonstrate a greater transcriptional response than HAM upon M.tb infection, with 2 to >10 times more genes up- or down-regulated. The results identify key genes involved in cellular responses to M.tb in two different human macrophage types. Follow-up bioinformatics analysis indicates that approximately 30% of response genes have expression quantitative trait loci (eQTLs in GTEx), common DNA variants that can influence host gene expression susceptibility or resistance to M.tb, illustrated with the TREM1 gene cluster and IL-10.

Dataset Information

Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.

Publications

Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.

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