Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders

Abstract

Evidence has accumulated that the occurrence of psychiatric disorders is related to chronic inflammation. In support of this linkage, changes in the levels of circulating pro-inflammatory cytokines and chemokines in the peripheral blood (PB) of psychiatric patients as well as correlations between chronic inflammatory processes and psychiatric disorders have been described. Furthermore, an inflammatory process known as "sterile inflammation" when initiated directly in brain tissue may trigger the onset of psychoses. In this review, we will present the hypothesis that prolonged or chronic activation of the complement cascade (ComC) directly triggers inflammation in the brain and affects the proper function of this organ. Based on the current literature and our own work on mechanisms activating the ComC we hypothesize that inflammation in the brain is initiated by the mannan-binding lectin pathway of ComC activation. This activation is triggered by an increase in brain tissue of danger-associated molecular pattern (DAMP) mediators, including extracellular ATP and high-mobility group box 1 (HMGB1) protein, which are recognized by circulating pattern-recognition receptors, including mannan-binding lectin (MBL), that activate the ComC. On the other hand, this process is controlled by the anti-inflammatory action of heme oxygenase 1 (HO-1). In this review, we will try to connect changes in the release of DAMPs in the brain with inflammatory processes triggered by the innate immunity involving activation of the ComC as well as the inflammation-limiting effects of the anti-inflammatory HO-1 pathway. We will also discuss parallel observations that during ComC activation subsets of stem cells are mobilized into PB from bone marrow that are potentially involved in repair mechanisms.

Keywords: complement cascade; heme oxygenase 1; mannan-binding lectin; stem cell mobilization; sterile inflammation.

Figure 1

Proposed by us MBL-induced three-step model for triggering sterile inflammation in the brain tissue. All three phases of the complement cascade (ComC) activation process (initiation-, amplification-, and execution phase) are depicted here. In Step I (initiation phase), activation of microglia, astrocytes, and monocytes induces the release of danger-associated molecular pattern molecules (DAMPs) (ATP and high-mobility group box 1), and the secretion of ROS by these cells exposes neo-epitopes. Both DAMPs and neo-epitope–IgM complexes are recognized by mannose-binding lectin (MBL), which activates the ComC and CoaC in a MASP-1 and -2 dependent manner in Step II (amplification phase). In Step III (execution phase), the C5 cleavage fragments anaphylatoxins C5a and desArgC5a promote sterile inflammation in the brain, and this process is negatively regulated by heme oxygenase 1 (HO-1).

Figure 2

Proposed concept of stem cell trafficking between bone marrow (BM) and brain under steady-state conditions and in psychotic disorders. (A) Under steady-state conditions, stem cells, including hematopoietic stem cells (HSCs), multipotent stromal cells (MSCs), endothelial progenitor cells (EPCs), and the rare population of VSELs, circulate in PB at very low levels. (B) The numbers of these cells in PB under stress and in pathological situations increase in response to chemoattractants (e.g., sphingosine-1-phosphate, S1P; or stromal-derived factor 1, SDF-1) as well as stem cell trafficking modulators (e.g., the complement cascade (ComC) cleavage fragments C3a and C5a) that are released during the inflammation process from BM as well as from damaged brain.