Lung megakaryocytes are immune modulatory cells
Daphne N. Pariser, … , James Palis, Craig N. Morrell
Daphne N. Pariser, … , James Palis, Craig N. Morrell
Published October 20, 2020
Citation Information: J Clin Invest. 2021;131(1):e137377. https://doi.org/10.1172/JCI137377.
View: Text | PDF
Research Article Hematology Inflammation

Lung megakaryocytes are immune modulatory cells

Abstract

Although platelets are the cellular mediators of thrombosis, they are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered bone marrow–resident (BM-resident) cells. However, platelet-producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared with BM Mks. We therefore sought to define the immune functions of lung Mks. Using single-cell RNA sequencing of BM and lung myeloid-enriched cells, we found that lung Mks, which we term MkL, had gene expression patterns that are similar to antigen-presenting cells. This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment, as evidenced by BM Mks having an MkL-like phenotype under the influence of pathogen receptor challenge and lung-associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4+ T cell activation in an MHC II–dependent manner both in vitro and in vivo. These data indicated that MkL had key immune regulatory roles dictated in part by the tissue environment.

Authors

Daphne N. Pariser, Zachary T. Hilt, Sara K. Ture, Sara K. Blick-Nitko, Mark R. Looney, Simon J. Cleary, Estheany Roman-Pagan, Jerry Saunders II, Steve N. Georas, Janelle Veazey, Ferralita Madere, Laura Tesoro Santos, Allison Arne, Nguyen P.T. Huynh, Alison C. Livada, Selena M. Guerrero-Martin, Claire Lyons, Kelly A. Metcalf-Pate, Kathleen E. McGrath, James Palis, Craig N. Morrell

×

Figure 4

In vivo regulators of lung Mk phenotype.

Options: View larger image (or click on image) Download as PowerPoint
In vivo regulators of lung Mk phenotype. (A) IL-33 promoted lung Mk immu...
(A) IL-33 promoted lung Mk immune differentiation in vivo. Mice were treated with Mk-depleting antibody or control IgG. Mice were then treated with either ST2-Fc as an IL-33 blocking agent or control IgG. Recovering Mks had increased MHC II that was greatly attenuated by IL-33 blocking (unpaired t test). (B) P0 mice were treated with IgG or ST2-Fc and on P7 the lung Mk immune phenotype determined. IL-33 blocking reduced postnatal lung Mk immune differentiation (unpaired t test). (C and D) BM Mk immune phenotype plasticity in vivo. BM Mks were isolated, labeled with CFSE, and o.p. delivered to control mice. (C) Two days and (D) 5 days later transferred BM Mk MHC II and CCR7 levels were determined. BM-transferred BM Mks had increased immune molecule expression in the lung environment. After 5 days (D), BM Mk cells transferred to the lung were also identified in the BM and had reduced immune molecule expression compared with those transferred and in the lung (1-way ANOVA with Tukey’s multiple-comparison test). *P = 0.01 to 0.05; **P = 0.001 to 0.01; ***P = 0.0001 to 0.001; ****P < 0.0001.