Counting the Toll of Inflammation on Schizophrenia-A Potential Role for Toll-like Receptors

Abstract

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that are ubiquitously expressed in the human body. They protect the brain and central nervous system from self and foreign antigens/pathogens. The immune response elicited by these receptors culminates in the release of cytokines, chemokines, and interferons causing an inflammatory response, which can be both beneficial and harmful to neurodevelopment. In addition, the detrimental effects of TLR activation have been implicated in multiple neurodegenerative diseases such as Alzheimer's, multiple sclerosis, etc. Many studies also support the theory that cytokine imbalance may be involved in schizophrenia, and a vast amount of literature showcases the deleterious effects of this imbalance on cognitive performance in the human population. In this review, we examine the current literature on TLRs, their potential role in the pathogenesis of schizophrenia, factors affecting TLR activity that contribute towards the risk of schizophrenia, and lastly, the role of TLRs and their impact on cognitive performance in schizophrenia.

Keywords: Toll-like receptor; cognition; inflammation; schizophrenia.

Figure 1

Figure illustrating the hypothesis of TLR pathway and signalling leading to cognitive deficits in patients suffering from schizophrenia. ROS—reactive oxygen species, DAMPs—damage associated molecular patterns, TLR—Toll-like receptor, LTP—long term potentiation, CaMKIIα—calcium-calmodulin dependent kinase II alpha, IFITM3—interferon-induced transmembrane protein 3, MyD88—myeloid differentiation primary response 88 protein, IRAK—interleukin-1 receptor-associated kinase, TRAF—tumour necrosis factor receptor (TNFR)-associated factor 6, TRIF—TIR-domain-containing adapter-inducing interferon-β, TRAM—TRIF-related adaptor molecules, TAK—transforming growth factor-β (TGF-β)-activated kinase 1, TAB—TAK1 binding protein 1, IKK—IκB kinase, IκB—inhibitor of nuclear factor kappa B (NF-κB), MAPK— Mitogen-activated protein kinase, ERK—extracellular signal-regulated protein kinase, JNK—c-Jun N-terminal kinase, RIP—receptor-interacting protein, IRF—interferon regulatory factor, AP-1—activator protein 1. “Created with BioRender.com (accessed on: 16 May 2023)”.