Study highlights the role of hematopoietic immune cells in gene regulation

More often, the human body is viewed as a “machine” containing specialized components: immune cells protect against pathogens, organs contribute physiological functions, and soft tissue and bones give structure.

First authors Nikolaus Fortelny and Thomas Krausgruber with senior author Christoph Bock. Image Credit: © Klaus Pichler/CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.

Several types of cells and organs may have more than one role to play. At CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, (CeMM) scientists have now found a remarkable example of multi-tasking cells.

In a study published in the scientific journal Nature, CeMM scientists have examined the transcriptional and epigenetic regulation in structural cells, such as fibroblasts, endothelium, and epithelium.

The team identified an extensive activity of immune genes, indicating that structural cells are greatly involved in the body’s reaction to microbes. The study further exposed an “epigenetic potential” that pre-programs structural cells to take part in the immune response against the microbes. Such findings emphasize an underrated component of the immune system and pave the way for an interesting area for research and upcoming treatments.

The immune system is known to safeguard the human body from continuous attacks by bacteria, viruses, and other microbes. A large part of this protection is offered by hematopoietic immune cells, which are obtained from the bone marrow and specialize in combating microbes.

Hematopoietic immune cells contain macrophages, which eliminate pathogens. These include T cells, which destroy infected virus-producing cells, and B cells-producing antibodies, which neutralize the microbes.

But immune functions are not limited to these “specialists,” and several more cell types can sense when they are infected, and play a role in the immune response against microbes.

Structural cells offer the body’s essential building blocks and play a significant role in molding the structure of organs and tissues. Most specifically, epithelial cells represent the surface of the skin, which also keeps tissues and organs apart from one another, endothelial cells line the interior of all blood vessels, and fibroblast offers the connective tissue that maintains the shape of the organs and tissues.

Structural cells are generally considered as simple and rather dull components of the body, in spite of their well-established functions in cancer and autoimmune disorders, such as inflammatory bowel disease and rheumatoid arthritis.

In their recent study, Thomas Krausgruber, Nikolaus Fortelny, and collaborators in Christoph Bock’s laboratory at CeMM focused on describing the function of structural cells in immune regulation by following a methodical, genome-wide analysis of epigenetic and transcriptional regulation of structural cells found in the body.

In this context, the CeMM scientists established a detailed catalog of immune gene activity in structural cells, implementing high-throughput sequencing technology (ChIPmentation, ATAC-seq, and RNA-seq) on three structural cell types (fibroblasts, endothelium, and epithelium) from 12 different organs of healthy mice.

This dataset exposed the extensive-expression of immune genes in structural cells and also highly organ-specific and cell-type-specific patterns of the regulation of genes.

Through bioinformatic analysis, genes that regulate a complex network of communications between hematopoietic immune cells and structural cells were detected. This indicates promising mechanisms through which structural cells contribute to the response to pathogens.

Fascinatingly, several immune genes revealed epigenetic signatures that are usually related to high expression of genes, whereas the observed expression in structural cells acquired from healthy mice was lower than predicted on the basis of their epigenetic signatures.

Hence, CeMM scientists assumed that these genes are epigenetically pre-programmed for quick upregulation when their activity is required—for instance, in response to a microbe. To verify this concept, the scientists connected forces with Andreas Bergthaler’s laboratory-based at CeMM, banking on their know-how in infection biology and viral immunology.

When a virus (LCMV) triggering a broad immune response infects the mice, several of those genes that were epigenetically set for activation become upregulated and play a role in the transcriptional changes that are exhibited by structural cells in response to viral infections.

These outcomes indicate that structural cells adopt an “epigenetic potential” that pre-programs them to take part in quick immune responses. As further validation, the team activated an artificial immune response by administering cytokines into mice, and they did find that a number of same kinds of genes were upregulated.

The latest study has exposed a remarkable complexity of the regulation of immune genes in structural cells. Such results emphasize that structural cells are essential building blocks of the body and also contribute broadly to its defense against microorganisms.

Furthermore, the presented data represent a major initial step toward interpreting what “structural immunity” may actually mean for the immune system, and may help develop novel treatments for some of the various diseases in which the immune system is involved.