Megakaryocytes Display Innate Immune Cell Functions and Respond during Sepsis

Abstract

24 Megakaryocytes (MKs) are precursors to platelets, the second most abundant cells in the 25 peripheral circulation. However, while platelets are known participate in immune responses and 26 play significant roles during infections, the role of MKs within the immune system has not been 27 explored. Here we utilize in vitro techniques to show that both cord blood-derived MKs (CB 28 MKs) and MKs from a human megakaryoblastic leukemia cell line (Meg-01) chemotax towards 29 pathogenic stimuli, phagocytose bacteria, and release chromatin webs in response to bacteria.30 Moreover, in patients with sepsis, we found that MK counts were significantly higher in the 31 peripheral blood, and CD61 + staining was increased in the kidneys and lungs, correlated with the 32 development of organ dysfunction. Overall, our study suggests that MK cells display basic innate 33 immune cell functions and respond during infections and sepsis.3 34 Megakaryocytes (MKs) are commonly recognized as key participants in hemostatic processes 35 through the production of platelets 1-2 . In addition to their presence in the bone marrow, MKs can 36 also be located in the lungs, lymph nodes, spleen, and liver during extra medullary hematopoiesis 3-37 7 . MKs have also been reported to be significantly increased in the lungs during severe pulmonary 38 inflammation, such as acute respiratory distress syndrome (ARDS), when they are believed to 39 promote inflammation via the release of platelets [8][9][10] . The current paradigm by which MKs are 40 increased in the lungs during ARDS revolves around MKs passive escape from the bone marrow, 41 entrance to arterial circulation, and passive mechanical entrapment within the microcirculatory bed 42 of the alveoli 4,11-12 . 4344 The participation of MKs in immune responses is suggested by several anecdotal observations 19 .45 Maturing MKs express both major histocompatibility complex (MHC) class I and II molecules 46 and a variety of toll-like receptors (TLRs) on their cell surface [13][14][15][16][17][18][19] . MKs, just like platelets, also 47 contain various granule types, including lysosomes, which participate in the endocytosis and 48 degradation of pathogens 20 . MKs can play antigen-presenting-cell (APC) roles and stimulate Th-49 17 responses in lupus 13,21 . Thrombocytes, the amphibian equivalent of the mammalian 50 MK/platelet, actively phagocytose live bacteria [23][24][25] . In mammals, MKs internalize viruses, 51 including dengue virus and HIV, and multiple case reports show evidence for MKs containing 52 fungi [26][27][28][29] . Although such reports provide sporadic support for an active role for MKs in the 53 immune responses, this function of MKs has not been tested systematically. 5455 Here, we show that the human MKs can engulf pathogens, release chromatin nets, and undergo 56 chemotaxis in gradients of standard chemoattractants. Moreover, we find that during sepsis, the 4 57 number of large CD61 + CD41 + cells increases in peripheral circulation, and the number of large 58 CD61 + cells in...

Pulmonary Megakaryocytes in Coronavirus Disease 2019 (COVID-19): Roles in Thrombi and Fibrosis

“…23 However, Frydman et al have shown that megakaryocytes can generate histone-decorated chromatin webs, which mimics the NETs. 10 This report also demonstrated increased CD61þ staining in the kidneys and lungs from patients with sepsis, which correlated with the development of organ dysfunction, an accompaniment often present in ARDS.…”

“… 9 Surface adhesion molecules expressed on megakaryocytes can assist in retention of these cells in the lungs, particularly when the pulmonary endothelium is activated by inflammation or infection. 10 Megakaryocytes also phagocytose bacteria and viruses and use their lysosomal granules as pathogen-eradicating bullets. 10 11 12 An additional immune role for megakaryocytes is reflected by their interaction with neutrophils, which occurs through the unique process called “emperipolesis.” 13 During emperipolesis, these leukocytes are engulfed by the megakaryocytes with no membrane disruption but allowing cellular material transfer between the cells.…”

“… 10 Megakaryocytes also phagocytose bacteria and viruses and use their lysosomal granules as pathogen-eradicating bullets. 10 11 12 An additional immune role for megakaryocytes is reflected by their interaction with neutrophils, which occurs through the unique process called “emperipolesis.” 13 During emperipolesis, these leukocytes are engulfed by the megakaryocytes with no membrane disruption but allowing cellular material transfer between the cells. 13 Although not shown specifically with megakaryocytes in the lung fields, in response to acute inflammation, megakaryocytes become activated and manufacture large quantities of platelets, which can then play a role in inflammatory conditions.…”