טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentChait Berman Karen
SubjectGlobal Architecture of the Neural-Immune Network in the
Periphery
DepartmentDepartment of Medicine
Supervisor Professor Shai Shen-Orr


Abstract

The immune system is composed of a complex set of molecular, cellular, and organismal networks that act in coordination to promote effective host defense from potential harm caused by infection, tissue injury or damage.  Immune response is influenced by external factors and signals of the local microenvironment, the endocrine system and the nervous system. The nervous system initiates an immune-modulatory response through different nerve pathways releasing neurotransmitters, neuropeptides and neuro-hormones that bind to their respective receptors expressed on the surface of immune cells.

Though a large number of neuronal signaling molecules are known, only a small fraction has been investigated with respect to how they may mediate the complex response of the immune system. Neuronal signals are communication mediators that can be released by neuronal and non-neuronal cells from different systems and with differing outcomes. Therefore, reviewing the neuronal signals effect on the immune system in a systemic manner will allow to understand how widespread and biologically important are neuronal-immune interactions in the regulation of immune homeostasis.

Here we analyzed public murine gene expression data of 170 sorted cell types across the entire hematopoietic lineage from 19 lymphoid organs and other tissues in the periphery in steady state conditions. We mapped the landscape of neuro-receptors on immune cells at high resolution identifying comprehensive signaling to all immune cell types occurring with high specificity between the neuronal signal and the target lineage. Furthermore, we observed co-expression relations between neuro-receptors with lineage specific expression and function, suggesting a coordinated network of neuro-receptors activated simultaneously and functioning in shared processes.

We constructed communication networks per tissue mapping interactions between cells expressing the neuronal ligand and cells expressing their receptors, allowing to decipher the architecture of neuro-immune-stromal interactions in a tissue dependent manner. We noticed that immune cells in the thymus are highly connected by neuronal signals to stromal cells, indicating that stromal cells are key regulators of the immune system in the thymus. We also identified the effect of neuronal signals in the immune intrinsic communication and were able to reconstruct a correct ordering of hematopoiesis based solely on neuro-receptor expression patterns on cells, suggesting that they play a yet unappreciated role in hematopoiesis. Collectively, these findings suggest that the alphabet vocabulary of immune regulation should be expanded to include neuronal signals.

This systems-level bioinformatics analysis provides a resource for studying the neural signaling effects on immune regulation and reveal novel targets with potent effect on the immune system.