TY - JOUR
T1 - Lung megakaryocytes are immune modulatory cells
AU - Pariser, Daphne N.
AU - Hilt, Zachary T.
AU - Ture, Sara K.
AU - Blick-Nitko, Sara K.
AU - Looney, Mark R.
AU - Cleary, Simon J.
AU - Roman-Pagan, Estheany
AU - Saunders, Jerry
AU - Georas, Steve N.
AU - Veazey, Janelle
AU - Madere, Ferralita
AU - Santos, Laura Tesoro
AU - Arne, Allison
AU - Huynh, Nguyen P.T.
AU - Livada, Alison C.
AU - Guerrero-Martin, Selena M.
AU - Lyons, Claire
AU - Metcalf-Pate, Kelly A.
AU - McGrath, Kathleen E.
AU - Palis, James
AU - Morrell, Craig N.
N1 - Funding Information:
This work was supported in part by grants from the NIH, Heart Lung and Blood Institute (R21HL153409, R01HL141106, R01HL142152, 5F31HL147458, 5F31HL145922), American Heart Association (18CSA34020064), and the University of Rochester Lung Biology Disease Program Pilot Award Program. We thank the University of Rochester Genomics Research Center for genetics/genomics studies.
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/1/4
Y1 - 2021/1/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098079881&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098079881&partnerID=8YFLogxK
U2 - 10.1172/JCI137377
DO - 10.1172/JCI137377
M3 - Article
C2 - 33079726
AN - SCOPUS:85098079881
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
M1 - e137377
ER -