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.

Complement activation contributes to perioperative neurocognitive disorders in mice

“…Under pathological conditions, excessive hippocampal C3 deposition has been implicated in the development of many neurological disorders [13, 14]. In the current model, we found an early and significant elevation of hippocampal C3 levels after orthopedic surgery, supporting the involvement of complement activation in the pathophysiology of PND.…”

Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse

“…In the case of TLR4, the best described DAMPs are fibrinogen, heat shock proteins 60–70 (HSP60-70), and high-mobility-group box protein 1 (HMGB-1) (Piccinini and Midwood, 2010). The implication of DAMPs in the process called “sterile inflammation” supports the view of TLR4 as a ubiquitous sentinel receptor and some authors have remarked the importance of such subtype of neuroinflammation in psychiatric disorders (Ratajczak et al, 2018). Indeed, in the last years, some evidence suggests a role of TLR4 in stress and stress-related neuropsychiatric diseases (Garcia Bueno et al, 2016).…”

Markers of Regenerative Processes in Patients with Bipolar Disorder: A Case-control Study

“…Immune dysfunctions can take the form of inflammatory changes in the CNS, and, even more frequently, a generalized inflammatory response [ 43 , 44 , 45 , 46 ]. A very compelling concept of “sterile inflammation” supports evidence that inflammatory responses are initiated directly in brain tissue of the CNS, triggered by prolonged or chronic activation of the complement cascade via the MBL-MASP pathway [ 47 ]. Given the chronic, relapsing/remitting course of BD, the activation of immune processes may also be linked to the phase of BD [ 48 ].…”