Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implications

Abstract

Schizophrenia is a highly complex and severe neuropsychiatric disorder with an unknown etiopathology. Evidence for a dysregulated immune system in both the risk for and progression of schizophrenia has recently been overwhelming. Importantly, chronic low-grade inflammation both in the periphery and central nervous system has been shown to contribute predominantly to the pathogenesis of schizophrenia in a subset of individuals. Inflammation in the central nervous system is mediated by a range of proinflammatory cytokines, resident immune cells such as microglia, and brain infiltrating peripheral immunocompetent cells, such as T lymphocytes. Recently, Th17 cells, a subset of T helper cells have emerged as crucial players in mucosal defense against infections. It is linked to atopic, inflammatory, and autoimmune disorders. The risk factors/mechanisms leading to low-grade inflammation in schizophrenia are diverse and include infectious agents, stress, trauma, environmental toxins, genetic vulnerability, physical inactivity, obesity, poor diet, and sleep disruption. Herein, we propose that fetal programming of cellular immune components driven by intrauterine adversity can lead to the generation of long-lasting effector/memory Th17 cells. Th17 cells can disrupt the blood-brain barrier, infiltrate the central nervous system, and, along with other cytokines and microglia, lead to neuroprogression through neuroinflammation in schizophrenia.

Keywords: IL-17 cytokine; Th17 cells; etiology; fetal; inflammation; neuroprogression; pathogenesis; schizophrenia.

Fig. 1.

Summary of functional roles of Th17 cells in physiology and pathophysiology.

Fig. 2.

Hypothetical model summarizing aspects of Th17 pathway–mediated immunopathogenesis of schizophrenia (IO&NS, Immuno-inflammatory, oxidative & nitrosative stress).