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.
Highlights
INTRODUCTIONWe will discuss the emerging picture of the interplay between the stressor inflammation-mediated activation of innate immunity, inflammation, and changes in the levels of inflammation markers and stem cells circulating in peripheral blood (PB), providing a mechanistic basis for the occurrence of psychiatric disorders
In this review, we will discuss the emerging picture of the interplay between the stressor inflammation-mediated activation of innate immunity, inflammation, and changes in the levels of inflammation markers and stem cells circulating in peripheral blood (PB), providing a mechanistic basis for the occurrence of psychiatric disorders.It is well known that patients suffering from psychotic disorders often exhibit inflammationrelated abnormalities in PB, including (i) elevated levels of circulating pro-inflammatory cytokines and chemokines, (ii) increased numbers of circulating monocytes and neutrophils, as well as (iii) enhanced reactivity of microglia, astrocytes, and endothelial cells to various pro-inflammatoryInnate Immunity and Psychiatric Disorders signals [1,2,3,4]
We will discuss results indicating that stem cells are mobilized from bone marrow (BM) into PB as a result of complement cascade (ComC) activation [9,10,11,12], which might be potentially involved in certain repair mechanisms in the central nervous system (CNS)
Summary
We will discuss the emerging picture of the interplay between the stressor inflammation-mediated activation of innate immunity, inflammation, and changes in the levels of inflammation markers and stem cells circulating in peripheral blood (PB), providing a mechanistic basis for the occurrence of psychiatric disorders. Severe depression is often comorbid with chronic inflammatory conditions, and patients with preexisting inflammatory diseases are more susceptible to developing mood disorders than healthy individuals [5, 6] These findings support the existence of crosstalk between the central nervous system (CNS) and innate and adaptive immunity, which can be explained, at least partially, by the co-evolution of both systems. One can envision that understanding and controlling these mutual interactions between the immune and nervous systems could be a fundamental step in preventing some CNS diseases, including cerebral neuropathies (bipolar disorder, schizophrenia, major depressive disorder, autism, Alzheimer’s disease, Parkinsonism, epilepsy, and migraine) This possibility will be discussed in this review in the context of innate immunity-mediated inflammatory processes and the anti-inflammatory negative-feedback loops maintained by heme oxygenase 1 (HO-1). We will discuss results indicating that stem cells are mobilized from bone marrow (BM) into PB as a result of ComC activation [9,10,11,12], which might be potentially involved in certain repair mechanisms in the CNS
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