Abstract
In contrast to lipopolysaccharide (LPS)-induced preconditioning, which has repeatedly been examined in the past, the effects of post-ischemic LPS-induced sepsis, although clinically considerably more important, have not systemically been studied. We exposed mice to transient intraluminal middle cerebral artery occlusion (MCAO) and examined the effects of intraperitoneal LPS (0.1 or 1 mg/kg) which was administered 24 h post-ischemia. Post-ischemic glial reactivity, neuronal survival and neurological outcome were differently modulated by the higher and the lower LPS dose. Although both doses promoted neuronal survival after 72 h, the underlying mechanisms were not similar. Mice receiving 1 mg/kg LPS exhibited transient hypothermia at 1 and 3 hours post sepsis (hps), followed by reduced focal neurological deficits at 24, 48 and 72 hps. The lower dose (0.1 mg/kg) did not induce hypothermia, but reduced microglia/macrophage activation with the appearance of an anti-inflammatory CD206 positive cell phenotype in the brain parenchyma. Together, our results indicate a novel, dose-dependent modulation of microglial cells that is intricately involved in brain protection.
Highlights
Lipopolysaccharide (LPS) is a major component of the outer membrane of gram-negative bacteria, such as Escherichia coli
The sections obtained from the Bregma level, i.e., the core of the middle cerebral artery territory, were stained with chicken anti-neuronal nuclei (NeuN; 1:300; ABN91, MerckMillipore, Darmstadt, Germany), rabbit anti-dopamine and cAMP-regulated neuronal phosphoprotein (Darpp-32; 1:300; MA5-14968, Thermo Fisher Scientific, Waltham, MA, USA), rabbit anti-ionized calcium-binding adaptor protein (Iba-1; 1:500; 019-19741, Fujifilm Wako-Chemicals, Neuss, Germany) and mouse anti-glial fibrillary acidic protein (GFAP) conjugated to Alexa Fluor-555 (1:300; 3656s, Cell Signaling Technology, Frankfurt, Germany)
We observed no significant changes in the general neurological deficit score (Figure 1E), the higher dose of LPS (1 mg/kg) reduced focal deficits starting at 24 hps (F(2,20) = 3.8, p < 0.05; Figure 1F)
Summary
Lipopolysaccharide (LPS) is a major component of the outer membrane of gram-negative bacteria, such as Escherichia coli. LPS delivery induces a febrile response in rats and guinea pigs (Sehic and Blatteis, 1996; Bao et al, 2018) but not in mice. LPS is considered an attractive model of gram-negative sepsis-like states. Post-ischemic LPS delivery exacerbated systemic inflammatory responses, increased infarct volume and increased neurological deficits (Yousuf et al, 2013). Microglial and Astrocytic Responses in LPS-Induced Sepsis (MCAO), LPS delivery before ischemia confered protection via inflammatory pre-conditioning in rats and mice (Bastide et al, 2003; Rosenzweig et al, 2004). To elucidate the effects of post-ischemic LPS administration, we exposed mice to transient intraluminal MCAO, evaluating the effects of two LPS doses, 0.1 mg/kg and 1 mg/kg, on ischemic injury, astrocytic and microglial responses
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