IRAK4 Inhibition Attenuates Interleukin‐1‐Induced Astrogliosis: A Potential Therapeutic Target for Neurodegenerative Disorders?

Abstract

The activation of inflammatory signaling in the central nervous system (CNS) is a common component of many neurodegenerative conditions including traumatic brain injury (TBI), a disease for which there are currently no FDA‐approved pharmacotherapies. Inflammation orchestrates alterations in the astrocytic transcriptome, driving the process of astrogliosis and formation of A1‐type neurodegenerative astrocytes; an effect stemming in part from interleukin‐1 (IL‐1)‐mediated signaling. We hypothesize that IL‐1‐mediated activation of functional, astrocytic type 1 interleukin‐1 receptors (IL‐1R1) promotes reactive astrogliosis and neurotoxic A1‐type astrocyte formation following TBI. Further, we hypothesize that pharmacologically targeting astrocyte specific IL‐1R1‐mediated signaling may be effective in mitigating reactive astrogliosis and neurodegeneration inherent to TBI. In vivo, blast‐induced TBI rapidly increased cortical mRNA expression of interleukin‐1α (il‐1α), interleukin‐1β (il‐1β), il‐1r1 and glial fibrillary acidic protein (gfap). In vitro studies using murine astrocytes (ATCC, C8‐D1A) were used to characterize astrocyte‐specific responsiveness to direct, recombinant IL‐1α and IL‐1β exposure. IL‐1α and IL‐1β treatment increased gfap expression, indicative of significant astrocyte activation. Increased expression of il‐1r1 was also detected following IL‐1α or IL‐1β treatment of murine astrocytes in vitro, revealing an astrocyte‐specific positive feedback mechanism. IL‐1α treatment increased the expression of A1‐type astrocyte marker serping1, whereas IL‐1β treatment was found to dose‐dependently reduce serping1 expression. Interleukin‐1 receptor associated kinase‐4 (IRAK4), a kinase downstream of IL‐1R1 activation, is amenable to targeting with small molecule inhibitors. We hypothesized that IRAK4 may be a viable target for blocking IL‐1R1‐mediated signaling in astrocytes. Treatment of astrocytes with the selective IRAK4 inhibitor, AS2444697, attenuated IL‐1α‐induced increases in gfap, il‐1r1 and serping1 expression, indicative of a blockade of both reactive astrogliosis and the formation of neurotoxic astrocytes. Studies contained here provide the first evidence that the inhibition of IRAK4 may represent a potential strategy to inhibit the formation of neurotoxic A1‐type astrocytes in various neurodegenerative disorders, including TBI. Future studies will utilize in vivo murine models affording the conditional elimination and restoration of IL‐1R1 in astrocytes to better understand the role of IL‐1R1 signaling in TBI. Systematic characterization of the role of IRAK4 in the formation of A1‐type astrocytes will lead to a better understanding of how IL‐1R1 signaling contributes to the acute and chronic neurologic sequelae of TBI. Combined, these studies identify a potentially viable pharmacotherapeutic target required for IL‐1R1‐initiated signaling within astrocyte populations.Support or Funding InformationStudies were supported by the Brain & Behavior Research Foundation, PhRMA Foundation, and the University of Cincinnati.