The brain-immune cells axis controls tissue specific immunopathology

Abstract

During viral infections, cell death can be induced as a direct result of cytopathic virus replication in various cell types and tissues or as an immune response of the host to the infectious agent. This leads to an infiltration of inflammatory cells, causing subsequent tissue damage. The balance between effective elimination of the pathogen and prevention of fatal tissue damage is decisive for life. The host has developed various mechanisms to inhibit excessive immune responses.

Fig. 1

Viral induction of the HPA axis increases GC levels. The HPA axis is activated early during infection with viruses, such as human  cytomegalovirus (CMV), and murine MCMV through the release of innate cytokines. Induction of the HPA leads to secretion of CRH from the hypothalamus that in turn activates the distribution of adrenocorticosterone hormone (ACTH) from the anterior pituitary. Subsequently, ACTH promotes the adrenal cortex to release GCs

Fig. 2

Endogenous GCs and the cytokine microenvironment decide about tissue pathology and pathogen elimination. Viral induction of the HPA leads to secretion of endogenous GCs. The cytokine microenvironment, especially the presence/absence of IL-12 and IL-15, together with the secreted GCs mediate tissue-specific PD-1 expression on splenic NK cells. In the liver, high-IL-12 levels lead to PD-1^neg NK cells, whereas elevated IL-15 presence in the spleen activated a high proportion of NK cells to express PD-1 on their surface. Subsequently, PD-1 expression limits the secretion of the pro-inflammatory cytokine interferon gamma (IFN-γ), especially in the spleen, preserving tissue integrity and promoting effective pathogen elimination. In contrast, absence of this pathology preventive pathway leads to high-IFN-γ levels causing severe tissue damage and inflammation. Hence, activation of this neuroendocrine pathway sustains tissue integrity and effective pathogen elimination