Abstract
The interleukin-1 receptor type 1 (IL-1R1) holds pivotal roles in the immune system, as it is positioned at the “epicenter” of the inflammatory signaling networks. Increased levels of the cytokine IL-1 are a recognized feature of the immune response in the central nervous system (CNS) during injury and disease, i.e., neuroinflammation. Despite IL-1/IL-1R1 signaling within the CNS having been the subject of several studies, the roles of IL-1R1 in the CNS cellular milieu still cause controversy. Without much doubt, however, the persistent activation of the IL-1/IL-1R1 signaling pathway is intimately linked with the pathogenesis of a plethora of CNS disease states, ranging from Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), all the way to schizophrenia and prion diseases. Importantly, a growing body of evidence is showing that blocking IL-1R1 signaling via pharmacological or genetic means in different experimental models of said CNS diseases leads to reduced neuroinflammation and delayed disease progression. The aim of this paper is to review the recent progress in the study of the biological roles of IL-1R1, as well as to highlight key aspects that render IL-1R1 a promising target for the development of novel disease-modifying treatments for multiple CNS indications.
Highlights
One of the most well-established groups of cytokines capable of orchestrating inflammatory responses by inducing the expression of pro-inflammatory molecules in both peripheral (PNS) and central nervous system (CNS) environments is the interleukin-1 (IL-1) family
We review what we see as major advances in the understanding of the roles of interleukin-1 receptor type 1 (IL-1R1) in the CNS, the cellular signaling mechanisms of IL-1R1 and current pharmacotherapy, as well as recent evidence strongly suggesting that IL-1R1 may be an important modulator in the CNS under pathophysiological conditions
While the exact mechanisms by which IL-1R1 operates in the brain remain elusive, it is clear that the function of this protein extends beyond the CNS diseases highlighted on the above sub-sections
Summary
One of the most well-established groups of cytokines capable of orchestrating inflammatory responses by inducing the expression of pro-inflammatory molecules in both peripheral (PNS) and central nervous system (CNS) environments is the interleukin-1 (IL-1) family. Within this group, the first interleukin ever purified, IL-1, is found in two distinct isoforms: IL-1α and IL-1β [1,2]. IL-1R1 is a membranebound protein that may be cleaved by matrix metalloproteases to a soluble, circulating form Both the membrane-bound and the soluble forms of IL-1R1 are biologically active, regulating the inflammatory response through agonistic and antagonistic modulation of cytokine activity [5,6]. We review what we see as major advances in the understanding of the roles of IL-1R1 in the CNS, the cellular signaling mechanisms of IL-1R1 and current pharmacotherapy, as well as recent evidence strongly suggesting that IL-1R1 may be an important modulator in the CNS under pathophysiological conditions
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