Immune signatures of megakaryocytes in persistent inflammation-immunosuppression and catabolism syndrome

Abstract

Persistent inflammation-immunosuppression and catabolism syndrome (PICS) is a severe condition that may follow sepsis and is characterized by ongoing inflammation and immune suppression, diminishing quality of life and potentially causing death. The role of megakaryocytes (MKs) in PICS, despite their association with thrombopoiesis, is not well understood. In this study, we use single-cell RNA sequencing to profile MKs in peripheral blood mononuclear cell samples obtained from 11 patients, including six with PICS, five with sepsis, and five healthy controls, to determine the diversity and molecular signatures of the MKs. Five subgroups of MKs are identified (MK1–MK5), and their proportions vary across the groups. MK1 and MK2 are predominant in PICS. Gene Ontology analysis shows that genes related to antigen processing and presentation and IL-17 signaling are enriched in MK1, whereas genes associated with platelet degranulation and neutrophil activation are enriched in MK2. Moreover, the expression level of CCL5 is markedly increased in MKs. Ligand-receptor analysis reveals dynamic interactions among MKs and T cells, B cells, natural killer cells, monocytes, and macrophages, suggesting a broad role of MKs in immune homeostasis. In PICS model mice, MKs regulate systemic inflammation by reducing the levels of the proinflammatory cytokines TNF-α and IL-17A and promoting lung tissue repair. Our findings establish MKs as essential components of the immune system in PICS and provide new insights into their potential as therapeutic targets for post-sepsis immune dysfunction.

1. Introduction

Sepsis, a major cause of morbidity and mortality worldwide, can lead to multiple organ dysfunction and long-term immune alterations [1]. Individuals who survive sepsis may experience “persistent inflammation-immunosuppression, and catabolism syndrome” (PICS), a condition characterized by metabolic derangements, immune dysfunction, and increased susceptibility to secondary infections [2–4].

Although the precise mechanisms underlying PICS remain to be elucidated, elevated levels of C-reactive protein (CRP), myeloid-derived suppressor cells, and inflammatory cytokines, including interleukin (IL)-6 and IL-8, are associated with the pathogenesis of PICS [5]. Many previous studies have focused on the role of myeloid cells and lymphocytes in sepsis-induced immune suppression [1,6]. However, recent evidence suggests that megakaryocytes (MKs), which are traditionally considered to function as platelet progenitors [7–9], may contribute to immune regulation and inflammation in the PICS. MKs have been implicated in several inflammatory diseases, with roles in regulating neutrophil activation, modulating adaptive immunity, and contributing to the resolution of inflammation [10–12]. However, the heterogeneity and functional dynamics of MKs in pathological states are underexplored, and the precise role of MKs in PICS remains unclear.

Single-cell RNA sequencing (scRNA-seq) has revolutionized the characterization of cellular diversity, enabling the identification of novel immune cell subsets and their molecular signatures. In the present study, we systematically characterized the MKs of patients with PICS, septic patients, and healthy individuals using single-cell transcriptomics. The role of MKs in the immune response during PICS secondary to sepsis was also assessed. Our findings revealed extensive MK reprogramming in the PICS and suggested that MKs play an immunoregulatory role in the PICS, potentially influencing post-sepsis immune homeostasis. Our results provide a comprehensive overview of the role of MKs in the immune landscape of patients with PICS following sepsis.