The role of TLR/Inflammasome/Cytokine axis; Drawing the link between innate and adaptive neuroimmunology?

Introduction and Objectives: Toll-like receptors (TLRs) are innate immune receptors that contain ۱۳ classes, of which ۱۰ are found in humans. TLRs recognize pathogen associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Following stimulation by PAMPs/DAMPs, By the help of adaptor proteins such as MyD۸۸, TLRs initiate a downstream signaling cascade that culminates in nuclear factor kappa light chain enhancer of B-cells (NF-kB). This could lead to the activation of inflammasomes, key regulators of inflammation. Inflammasomes are complexes that mediate the production of cytokines such as IL-۱B and IL-۱۸ through canonical (casp۱ mediated) and non-canonical (casp۴/۵ mediated) pathways. Cytokines could affect the adaptive immune system, highlighting an innate/adaptive link. The present perspective highlights the role of the above-mentioned innate-adaptive immunological axis in neurological disorders. Also, genetic regulators which could influence this axis are discussed.Method: A comprehensive search was carried out in PubMed, Scopus, and Web of Science (WoS) using the key words “Toll-like receptors”, ‘Inflammasomes”, “NLRP”, “AIM۲”, “NLRC۴”, and “brain”, “neuro”. No restriction on language or date of search was considered.Result: TLRs are implicated in neuropsychiatric disorders, including epilepsy, neurodegenerative conditions, and neuropsychiatric problems. TLR۴-IRAK۱- NFκB axis is implicated in the early NLRP۳ inflammasome reply in peripheral blood mononuclear cells of Rett syndrome cases. Moreover, evidence has shown the role of TLRs and inflammasomes in neuropsychiatric conditions, such as autism, depression, seizures, and headaches. The TLR-inflammasome axis could be implicated in many conditions through affecting the polarization of the adaptive immune response. T-cell polarization and differentiation could be affected as a result of cytokine production which is implicated in a diverse range of neurological disorders. Also, the produced cytokines could affect the blood-brain barrier characteristics, which has been associated with many neuropathologies, including neurodegenerative disorders. The elements in the pathway could be regulated by non-coding RNAs which deserves further attention in future studiesConclusion: Investigating neuropsychiatric disorders through the described innate-adaptive neuroimmune axis could provide a great premise for future research. Drug discovery approaches could focus on the elements of such novel pathways, by taking into account multiple inflammasome complexes that work together through caspases-۱/۴/۵ to produce cytokines.

کلیدواژه ها:

Neuropsychiatry ، Neuroimmunology ، TLRs ، Innate-adaptive immune axis