Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1

Abstract

Memory impairment following West Nile virus neuroinvasive disease (WNND) is associated with loss of hippocampal synapses with lack of recovery. Adult neurogenesis and synaptogenesis are fundamental features of hippocampal repair, suggesting viruses impact these processes. Here, using an established model of WNND-induced cognitive dysfunction, transcriptional profiling revealed alterations in gene expression that limit adult neurogenesis, including interleukin (IL)-1. WNND-recovered animals exhibit decreased neuroblasts and increased astrogenesis, without recovery of hippocampal neurogenesis at thirty days. Analysis of cytokine production in ex vivo isolated microglia and astrocytes revealed the latter to be the predominant source of IL-1. IL-1R1-deficient, WNND-recovered mice exhibit normal neurogenesis, recovery of presynaptic termini, and resistance to spatial learning defects, the latter of which likewise occurred after treatment with IL-1R1 antagonist. Thus, preferential generation of proinflammatory astrocytes impairs neuronal progenitor cell homeostasis via expression of IL-1, which may underlie long-term cognitive consequences of WNND, but provides a therapeutic target.

Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity

“…In West Nile virus neuroinvasive disease (WNND), a condition associated with loss of hippocampal synapses and cognitive dysfunction, astrocytes were shown to be the predominant source of IL-1. In a mouse model of WNND, IL-1R1 deficiency was associated with normal neurogenesis, recovery of pre-synaptic termini, and resistance to spatial learning defects, indicating that pro-inflammatory astrocytes impair neuronal progenitor cell homeostasis via IL-1 overexpression (Garber et al, 2018).…”

“…In addition, depending on the concentration, IL-1 can facilitate neuronal survival by promoting the expression of nerve growth factors (NGFs) and other neurotrophic factors or impair neurogenesis, for instance by favoring the astrocyte rather than neuronal lineage (Garber et al, 2018;Liu and Quan, 2018).…”

“…In inflammatory or stress murine models IL-1b, produced by brain microglia in response to TLR activation, complement components, other cytokines (such as tumor necrosis factor-a [TNF-a]), and IL-1 itself (Dinarello, 2011), decreased neurogenesis, and influenced synaptic plasticity, processes that are vital for the development and retention of spatial memory (Garber et al, 2018;Tong et al, 2012).…”

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

“…These "irrational" phenomena can be caused by an overreaction and dysfunction of reactive astrocytes after brain injury, or due to the release of neurodeleterious molecules [78]. Astrocytes, therefore, hold both neuroprotective and neurodeleterious effects following TBI, making it a double-edged sword for neurorestoration [83][84][85]. This also indicates that we cannot simply suppress or promote reactive astrogliosis, but should selectively stimulate the beneficial effects and ameliorate the deleterious ones in the astrocytetargeting therapy [78].…”

Understanding the Role of Antiviral Cytokines and Chemokines on Neural Stem/Progenitor Cell Activity and Survival

“…In addition to reducing NSPC proliferation, IL-1b induces differentiation of NSPCs into the glial lineage and/or restricts differentiation into the neuronal lineage in vitro (23,29,45,68,142). This is also supported by in vivo studies where inhibition or knockout of interleukin 1 receptor 1 inhibits the decrease in neurogenesis in models of WNV neuroinvasive disease (44) and acute stress (66). Mechanistically, IL-1b-mediated astrogliogenesis may occur through STAT3 signaling and the suppression of multiple proneural basic helix-loop-helix transcription factors (23,68).…”