Systemic inflammation and microglial activation: systematic review of animal experiments.

Inge C.M Hoogland,David J Van Westerloo,Carin Houbolt,Willem A Van Gool,Diederik Van De Beek

doi:10.1186/s12974-015-0332-6

Abstract

BackgroundAnimal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated delirium. We systematically reviewed animal experiments related to the effects of systemic inflammation on the microglial and inflammatory response in the brain.MethodsWe searched PubMed between January 1, 1950 and December 1, 2013 and Embase between January 1, 1988 and December 1, 2013 for animal studies on the influence of peripheral inflammatory stimuli on microglia and the brain. Identified studies were systematically scored on methodological quality. Two investigators extracted independently data on animal species, gender, age, and genetic background; number of animals; infectious stimulus; microglial cells; and other inflammatory parameters in the brain, including methods, time points after inoculation, and brain regions.ResultsFifty-one studies were identified of which the majority was performed in mice (n = 30) or in rats (n = 19). Lipopolysaccharide (LPS) (dose ranging between 0.33 and 200 mg/kg) was used as a peripheral infectious stimulus in 39 studies (76 %), and live or heat-killed pathogens were used in 12 studies (24 %). Information about animal characteristics such as species, strain, sex, age, and weight were defined in 41 studies (80 %), and complete methods of the disease model were described in 35 studies (68 %). Studies were also heterogeneous with respect to methods used to assess microglial activation; markers used mostly were the ionized calcium binding adaptor molecule-1 (Iba-1), cluster of differentiation 68 (CD68), and CD11b. After LPS challenge microglial activation was seen 6 h after challenge and remained present for at least 3 days. Live Escherichia coli resulted in microglial activation after 2 days, and heat-killed bacteria after 2 weeks. Concomitant with microglial response, inflammatory parameters in the brain were reviewed in 23 of 51 studies (45 %). Microglial activation was associated with an increase in Toll-like receptor (TLR-2 and TLR-4), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) messenger ribonucleic acid (mRNA) expression or protein levels.InterpretationAnimal experiments robustly showed that peripheral inflammatory stimuli cause microglial activation. We observed distinct differences in microglial activation between systemic stimulation with (supranatural doses) LPS and live or heat-killed bacteria.

Highlights

The peripheral immune system has a strong effect on the brain as exemplified by the high incidence of delirium and the strongly increased risk for the development of dementia after systemic infections [1, 2]
Selection of articles Studies were included if they fulfilled the following criteria: (1) the study described an experiment where a peripheral infectious stimulus was administrated in animals, in vivo; (2) the study assessed the effects on microglia in the brain; (3) the effects on microglia were determined with specific microglial markers; (4) a group of control animals was described; (5) the study was an original full paper which presented unique data; and (6) the studies were published in English, French, or German
The microglial response of challenge with bacteria is less profound as compared to that found in the experiments using a challenge with supernatural LPS doses

Summary

Introduction

The peripheral immune system has a strong effect on the brain as exemplified by the high incidence of delirium and the strongly increased risk for the development of dementia after systemic infections [1, 2]. Peripheral (systemic) LPS challenge activates microglia, the major active immune cells in the central nervous system. Microglia can be in a resting state (morphologically “ramified”) or an activated state (morphologically “amoeboid”) [10]. Resting microglia survey their environment for damage, ready to support endangered neurons or to interfere with a potential threat to the tissue integrity. Animal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated delirium. We systematically reviewed animal experiments related to the effects of systemic inflammation on the microglial and inflammatory response in the brain

Methods

Results

Discussion

Conclusion