Megakaryocytes (MKs), known for their role in platelet production, have emerged as critical players in immune responses, showcasing versatility in both physiological and pathological contexts. Recent advances in technology have unveiled the diverse immune functions of MKs, which express immune sensors and participate in immune activities, thus expanding their traditional role beyond hemostasis and coagulation. This comprehensive review delves into the multifaceted immune roles of MKs, highlighting their distinct immunological roles under inflammatory conditions and their interactions with the immune system.

MKs exhibit cellular diversity, with subpopulations such as platelet-generating MKs, HSC niche MKs, and immune MKs, each with unique functional attributes. HSC niche MKs modulate HSC quiescence and proliferation, while immune MKs engage in immune responses. The review emphasizes the expression of immune receptors by MKs, such as toll-like receptors (TLRs), Fc gamma receptors (FcγRs), and CD40L, which enable them to detect pathogens and participate in innate and adaptive immunity. MKs also phagocytose fungi and bacteria, and can present antigens, suggesting their active role in immune surveillance.

Communication between MKs and other immune cells is a key aspect of their immune function. MKs secrete cytokines that influence B cell and plasma cell development, and they release microparticles that transport bioactive molecules, contributing to inflammation. The tissue-specific localization of MKs, such as in the lungs and spleen, shapes their immunological roles, with extramedullary MKs playing a role in immune surveillance and response.

In the context of inflammation, MKs serve as antiviral defenders and inflammation facilitators. They secrete interferons and upregulate IFN-induced transmembrane protein 3 (IFITM3), restricting viral entry and replication. However, an increased number of MKs correlates with disease severity in conditions like COVID-19, where they are associated with elevated cytokines and multiorgan injury. The dual role of MKs in viral infections underscores the balance between protective and pathogenic immune responses.

MKs also combat bacterial infections, with their numbers increasing in circulation during sepsis. They engage with bacteria both indirectly, through the release of pro-inflammatory platelets, and directly, through phagocytosis and the release of chromatin webs. The heterogeneity of MKs is further highlighted by the identification of an "immune MK" subpopulation, characterized by unique surface markers and gene expression profiles. This subpopulation is conserved across species, developmental stages, and tissues, and is involved in pathogen recognition, phagocytosis, and antigen presentation.

The review concludes by outlining future directions for "immune MK" research, including the exploration of the immune properties of platelets in relation to MK heterogeneity and the developmental origins of "immune MKs." The potential for "immune MKs" to influence disease outcomes and their interaction with other immune cells under various conditions is a promising area for future investigation. This review provides a thorough overview of the immunological face of megakaryocytes, emphasizing their complex and evolving role in immune responses and disease pathogenesis.
DOI: 10.1007/s11684-024-1087-1