IL-1RI (Interleukin-1 Receptor Type I) Signalling is Essential for Host Defence and Hemichannel Activity During Acute Central Nervous System Bacterial Infection

Abstract

Staphylococcus aureus is a common aetiological agent of bacterial brain abscesses. We have previously established that a considerable IL-1 (interleukin-1) response is elicited immediately following S. aureus infection, where the cytokine can exert pleiotropic effects on glial activation and blood–brain barrier permeability. To assess the combined actions of IL-1α and IL-1β during CNS (central nervous system) infection, host defence responses were evaluated in IL-1RI (IL-1 receptor type I) KO (knockout) animals. IL-1RI KO mice were exquisitely sensitive to intracerebral S. aureus infection, as demonstrated by enhanced mortality rates and bacterial burdens within the first 24 h following pathogen exposure compared with WT (wild-type) animals. Loss of IL-1RI signalling also dampened the expression of select cytokines and chemokines, concomitant with significant reductions in neutrophil and macrophage infiltrates into the brain. In addition, the opening of astrocyte hemichannels during acute infection was shown to be dependent on IL-1RI activity. Collectively, these results demonstrate that IL-1RI signalling plays a pivotal role in the genesis of immune responses during the acute stage of brain abscess development through S. aureus containment, inflammatory mediator production, peripheral immune cell recruitment, and regulation of astrocyte hemichannel activity. Taken in the context of previous studies with MyD88 (myeloid differentiation primary response gene 88) and TLR2 (Toll-like receptor 2) KO animals, the current report advances our understanding of MyD88-dependent cascades and implicates IL-1RI signalling as a major antimicrobial effector pathway during acute brain-abscess formation.

Critical role for the AIM2 inflammasome during acute CNS bacterial infection

“…Prior work from our laboratory demonstrated that IL‐1RI KO mice succumb to CNS S. aureus infection within the first 24 h following bacterial exposure (Xiong et al . ); therefore, we predicted that similar results would be observed for both NLRP3 and ASC KO animals, since this inflammasome platform has the largest range of molecular triggers leading to IL‐1β processing and release. Unexpectedly, ASC, but not NLRP3 KO mice were exquisitely sensitive to CNS S. aureus infection.…”

“…; Xiong et al . ). However, we did not detect any significant differences in peripheral leukocyte infiltrates or bacterial burdens between WT and ASC or AIM2 KO mice in this study, which may result from the combined actions of IL‐1β and IL‐1α loss in IL‐1RI KO animals in our previous report (Xiong et al .…”

“…; Xiong et al . ). Our prior studies utilizing IL‐1β and IL‐1RI knockout (KO) mice demonstrated a critical role for IL‐1 signaling during early brain abscess pathogenesis, as both mouse strains displayed marked susceptibility to infection and elevated bacterial burdens compared to wild‐type (WT) animals (Kielian et al .…”

“…; Xiong et al . ). Our recent report showed that microglial IL‐1β production in response to live S. aureus was mediated by the Nod‐like receptor protein 3 (NLRP3) inflammasome (Hanamsagar et al .…”

Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

“…As such, ATP that is released after CNS damage may not only act as an excitotoxic molecule, but it can also significantly contribute to inflammatory responses, thereby exacerbating the release of inflammatory cytokines. Proinflammatory cytokines TNF-a and IL1-b can furthermore reduce astroglial GJIC, while astroglial and microglial HCs and Panx1 channels are reported to open [45,52,336,[343][344][345][346]. It has been demonstrated in several scenarios, such as inflammatory conditions, ischemia and exposure to amyloid b, that a combined action of astrocytic Cx43 HCs, and microglial Cx43 HCs and Panx1 channels contributes to the reciprocal astrocyte-microglial communication and eventually to neuronal dysfunction [57,67,347,348].…”