Single-Cell Transcriptomics Reveals Compartment-Specific Differences in Immune Responses and Contributions for Complement Factor 3 in Hemorrhagic Shock Plus Tissue Trauma

• Published in: Shock (Augusta, Ga.) Ga.), 2021-12, Vol.56 (6), p.994-1008
• Main Authors: Fu, Guang, Chen, Tianmeng, Wu, Junru, Jiang, Ting, Tang, Da, Bonaroti, Jillian, Conroy, Julia, Scott, Melanie J., Deng, Meihong, Billiar, Timothy R.
• Format: Article
• Language: English
• Subjects: Animals; Complement C3 - immunology; Immunity, Cellular; Male; Mice; Mice, Inbred C57BL; Shock, Hemorrhagic - complications; Shock, Hemorrhagic - immunology; Transcriptome - immunology; Wounds and Injuries - complications; Wounds and Injuries - immunology
• ISSN: 1073-2322; 1540-0514
• DOI: 10.1097/SHK.0000000000001765

Hemorrhagic shock with tissue trauma (HS/T) leads to the activation of a system-wide immune-inflammatory response that involves all organs and body compartments. Recent advances in single-cell analysis permit the simultaneous assessment of transcriptomic patterns in a large number of cells making it feasible to survey the landscape of immune cell responses across numerous anatomic sites. Here, we used single-cell RNA sequencing of leukocytes from the blood, liver, and spleen to identify the major shifts in gene expression by cell type and compartment in a mouse HS/T model. At 6 h, dramatic changes in gene expression were observed across multiple-cell types and in all compartments in wild-type mice. Monocytes from circulation and liver exhibited a significant upregulation of genes associated with chemotaxis and migration and a simultaneous suppression of genes associated with interferon signaling and antigen presentation. In contrast, liver conventional DC exhibited a unique pattern compared with other myeloid cells that included a pronounced increase in major histocompatibility complex class II (MHCII) gene expression. The dominant pattern across all compartments for B and T cells was a suppression of genes associated with cell activation and signaling after HS/T. Using complement factor 3 (C3) knockout mice we unveiled a role for C3 in the suppression of monocyte Major Histocompatibility Complex class II expression and activation of gene expression associated with migration, phagocytosis and cytokine upregulation, and an unexpected role in promoting interferon-signaling in a subset of B and T cells across all three compartments after HS/T. This transcriptomic landscape study of immune cells provides new insights into the host immune response to trauma, as well as a rich resource for further investigation of trauma-induced immune responses and complement in driving interferon signaling.