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The article by Jenaldize et al. in this issue of Acta Psychiatrica Scandinavica examines plasma and cerebrospinal fluid (CSF) levels of the chemokine interleukin-8 (IL8) in suicide attempters with respect to healthy controls (1). It also analyses frequency distribution of a single nucleotide polymorphism in the promoter region of the IL8 gene. Using three different cohorts of suicide attempters and controls as sources of biological samples, the authors found a negative correlation between plasma and CSF levels of IL8 and scores of anxiety in suicide attempters, but not in controls. No additional effects were found in relation to depressive states. Notably, overall levels of IL8 did not differ between suicide attempters and controls. The second aspect of this study is the analysis of a genetic polymorphism in the promoter region of IL8, in which the allele in the position 251 before the start codon varies between an A or a T. The authors found that the T allele was more frequent in women who attempted suicide, with carriers of this allele having higher severity of anxiety. Thus, a strong negative correlation between anxiety and IL8 protein levels and the occurrence of a specific allele in suicide attempters suggests that these effects may represent a biologically relevant phenomenon underlying the pathophysiology of suicidal behaviour.
The rationale of the study is based on the widely reported association between inflammation, mood and anxiety disorders, and suicide. Accumulating evidence over the past several years includes many reports showing increased markers of systemic inflammation, including several proinflammatory cytokines and acute-phase proteins, in depression and suicide when compared with healthy controls (2). The general assumption in the field, although not always formally stated, is that peripheral circulating inflammatory molecules negatively affect brain function and mood through several mechanisms, including crossing the blood–brain barrier and acting on neurons and microglia, and altering HPA-axis function. A peripheral systemic inflammatory milieu is believed to reflect concurrent neuroinflammatory processes in the brain, which may contribute to the pathology of depression and suicide. In this context, a fundamental missing piece in the field is the lack of an acknowledged and well-characterized definition of what ‘neuroinflammation’ means in psychiatric conditions. While neuroinflammation is well defined in the context of infections, trauma, and autoimmune CNS disorders, psychiatric cases do not present a clear neuroinflammatory profile (3). This is reflected by the lack of consistent and reproducible data showing specific cellular and molecular inflammatory markers in the brain and CSF of most of major psychiatric illnesses. To this end, it is not clear whether neuroinflammation in psychiatry is a separate entity from classical inflammation and to what extent inflammatory markers are part of the pathophysiology, or whether they are simply byproducts of compensatory or partially related conditions. Importantly, recent evidence suggests that for some inflammatory molecules, such as IL8, a decrease in expression rather than an increase may be associated with disease pathology. Based on this, the authors propose that since as is expressed in the brain and believed to participate in important cellular processes, reductions below homeostatic levels may lead to pathological changes due to decreased activity (1). Indeed, chemokines such as IL8 are constitutively expressed in the brain and are involved in several homeostatic functions (4, 5). Remarkably, it is known that other inflammatory molecules, such as cytokines, also perform homeostatic functions in the brain (6, 7).
In short, cytokines and chemokines participate in basic neural cellular processes related to structural and functional plasticity, with critical roles in several brain functions, including learning, memory, and behavioural adaptation. Thus, reductions in the expression of these inflammatory molecules, often interpreted as anti-inflammatory and assumed as beneficial, may instead be pathological due to the lack of function. Therefore, alterations in the balance of a defined number of inflammatory molecules rather than generalized increases may be the signature of the neuroinflammatory pathology in psychiatry, which may have nothing to do with the classical concept of neuroinflammation seen in infectious and autoimmune disorders.
The occurrence of genetic variations in inflammatory genes, such as that reported in this study (1), is a common theme in the field of immunology. Polymorphisms in functional regions of the gene such as the promoter are likely linked with differential regulation of the gene and ultimately with protein expression and susceptibility to diseases. While it is likely that the reported polymorphism is associated with reduced levels of the protein and that this contributes to the pathology of anxiety, more research is needed to consolidate these findings. Nevertheless, this study is a promising starting point.