Abstract
Activation of microglial cells in response to brain injury and/or immune stimuli is associated with a marked induction of Toll-like receptors (TLRs). While in adult brain, the contribution of individual TLRs, including TLR2, in pathophysiological cascades has been well established, their role and spatial and temporal induction patterns in immature brain are far less understood. To examine whether infectious stimuli and sterile inflammatory stimuli trigger distinct TLR2-mediated innate immune responses, we used three models in postnatal day 9 (P9) mice, a model of infection induced by systemic endotoxin injection and two models of sterile inflammation, intra-cortical IL-1β injection and transient middle cerebral artery occlusion (tMCAO). We took advantage of a transgenic mouse model bearing the dual reporter system luciferase/GFP under transcriptional control of a murine TLR2 promoter (TLR2-luc-GFP) to visualize the TLR2 response in the living neonatal brain and then determined neuroinflammation, microglial activation and leukocyte infiltration. We show that in physiological postnatal brain development the in vivo TLR2-luc signal undergoes a marked ∼30-fold decline and temporal-spatial changes during the second and third postnatal weeks. We then show that while endotoxin robustly induces the in vivo TLR2-luc signal in the living brain and increases levels of several inflammatory cytokines and chemokines, the in vivo TLR2-luc signal is reduced after both IL-1β and tMCAO and the inflammatory response is muted. Immunofluorescence revealed that microglial cells are the predominant source of TLR2 production during postnatal brain development and in all three neonatal models studied. Flow cytometry revealed developmental changes in CD11b+/CD45+ and CD11b+/Ly6C+ cell populations, involvement of cells of the monocyte lineage, but lack of Ly6G+ neutrophils or CD3+ cells in acutely injured neonatal brains. Cumulatively, our results suggest distinct TLR2 induction patterns following PAMP and DAMP – mediated inflammation in immature brain.
Highlights
Neuroinflammation caused by infection, hypoxia-ischemia and stroke during the perinatal period contributes to increased risk for neurological and neuropsychiatric deficits and long term disabilities in children (Hagberg et al, 2015)
We report that TLR2 is highly expressed in early postnatal brain, between P6–postnatal day 9 (P9), that TLR2 expression rapidly decreases with postnatal brain maturation under physiological conditions and becomes restricted to the olfactory bulb at P28
We show that bacterial inflammation caused by systemic LPS injection induces TLR2 in microglial cells and promotes synthesis and/or secretion of inflammatory mediators, whereas sterile inflammation, induced by either intra-cortical IL-1β injection or transient middle cerebral artery occlusion (tMCAO), downregulates the innate immune response, limits TLR2 induction and blunts production of inflammatory cytokines
Summary
Neuroinflammation caused by infection, hypoxia-ischemia and stroke during the perinatal period contributes to increased risk for neurological and neuropsychiatric deficits and long term disabilities in children (Hagberg et al, 2015). Injury-induced inflammatory response is characterized by marked activation of the resident immune cells, microglial cells, and peripheral leukocytes, and production of inflammatory cytokines, events that may contribute to brain damage (Dirnagl et al, 1999; Iadecola and Anrather, 2011; Kriz and LalancetteHebert, 2009; Lo et al, 2003). Microglial cells are the principal immune cells of the brain. The current view is that once activated, microglial cells may acquire a variety of different stimulus- and context dependent immune profiles ranging from pro-inflammatory/cytotoxic to more alternative and neuroprotective phenotypes (Fernandez-Lopez et al, 2014; Pierre et al, 2017). Inflammation and microglial activation can actively contribute to both normal physiological development and to injury in neonatal brain
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