Abstract
Monocyte-derived alveolar macrophages drive lung injury and fibrosis in murine models and are associated with pulmonary fibrosis in humans. Monocyte-derived alveolar macrophages have been suggested to develop a phenotype that promotes lung repair as injury resolves. We compared single-cell and cytokine profiling of the alveolar space in a cohort of 35 patients with post-acute sequelae of COVID-19 who had persistent respiratory symptoms and abnormalities on a computed tomography scan of the chest that subsequently improved or progressed. The abundance of monocyte-derived alveolar macrophages, their gene expression programs, and the level of the monocyte chemokine CCL2 in bronchoalveolar lavage fluid positively associated with the severity of radiographic fibrosis. Monocyte-derived alveolar macrophages from patients with resolving or progressive fibrosis expressed the same set of profibrotic genes. Our findings argue against a distinct reparative phenotype in monocyte-derived alveolar macrophages, highlighting their utility as a biomarker of failed lung repair and a potential target for therapy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2097-2109 |
| Number of pages | 13 |
| Journal | Nature Immunology |
| Volume | 25 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2024 |
Funding
This research was supported in part through a generous gift from K. Querrey and L. Simpson. This work was supported, in part, by a generous gift from Mr. and Mrs. Ferro. This research was also supported by the computational resources and staff contributions provided for the Quest high-performance computing facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research and Northwestern University Information Technology. This research was also supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine and Feinberg\u2019s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University\u2019s high-performance computing facility, with the purpose of advancing research in genomics. We thank J. Milhans, A. Kinaci, S. Coughlin and all members of the Research Computing and Data Services team at Northwestern for their support. Northwestern University Flow Cytometry Core Facility is supported by the National Cancer Institute Cancer Center support grant (no. P30 CA060553) awarded to the Robert H. Lurie Comprehensive Cancer Center. Cell sorting was performed on a BD FACS Aria SORP cell sorter purchased with the support of the National Institutes of Health (NIH, grant no. 1S10OD011996-01). Integrative genomic services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Next-generation sequencing was performed with support from the Simpsons Querrey Institute for Epigenetics. J.I.B. was supported by NIH grants (nos. T32HL076139 and UL1TR001422). C.H.P. and R.B. were supported by NIH/National Institute on Aging (grant no. R01AG068579), Simons Foundation (grant no. 597491-RWC01) and the National Science Foundation (NSF, grant no. 1764421-01). C.H.P. was also supported by the NSF (grant no. DMS-1547394). N.S.M. was supported by the American Heart Association (grant no. 24PRE1196998). Raul S.J.E. was supported by the NIH (grant no. 5R21LM013670). G.R.W. was supported by the NIH (grant nos. P01HL114501 and R01HL116931) and grants from the Department of Defense and Boehringer Ingelheim. A.B. was supported by the NIH (grant nos. R01HL147290, R01HL145478 and R01HL147575). R.A.G. was supported by the NIH (grant no. 1F31AG071225), Simpson Querrey Fellowship in Data Science as Kimberly Querrey Fellow and Schmidt Science Fellows program, in partnership with the Rhodes Trust. R.M.T. was supported by the NIH (grant nos. R01ES034350 and R01ES027574). K.M.G. was supported by the NIH (grant no. R01ES028829). J.I.S. was supported by the NIH (grant nos. R01HL173987, P01HL154998 and P01AG049665). K.M.R. was supported by the NIH (grant nos. P01HL154998 and P01AG049665). G.R.S.B. was supported by a Chicago Biomedical Consortium grant, Northwestern University Dixon Translational Science Award, Simpson Querrey Lung Institute for Translational Science, the NIH (grant nos. P01AG049665, P01HL154998, U54AG079754, R01HL147575, R01HL158139, R01HL147290, R21AG075423 and U19AI135964) and the Veterans Administration (award no. I01CX001777). A.V.M. was supported by the NIH (grant nos. U19AI135964, P01AG049665, P01HL154998, U19AI181102, R01HL153312, R01HL158139, R01ES034350 and R21AG075423). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology