Dataset Information

Inflammatory monocytes and microglia play independent roles in inflammatory ictogenesis.

ABSTRACT:

Background

The pathogenic contribution of neuroinflammation to ictogenesis and epilepsy may provide a therapeutic target for reduction of seizure burden in patients that are currently underserved by traditional anti-seizure medications. The Theiler's murine encephalomyelitis virus (TMEV) model has provided important insights into the role of inflammation in ictogenesis, but questions remain regarding the relative contribution of microglia and inflammatory monocytes in this model.

Methods

Female C57BL/6 mice were inoculated by intracranial injection of 2 × 10⁵, 5 × 10⁴, 1.25 × 10⁴, or 3.125 × 10³ plaque-forming units (PFU) of the Daniel's strain of TMEV at 4-6 weeks of age. Infiltration of inflammatory monocytes, microglial activation, and cytokine production were measured at 24 h post-infection (hpi). Viral load, hippocampal injury, cognitive performance, and seizure burden were assessed at several timepoints.

Results

The intensity of inflammatory infiltration and the extent of hippocampal injury induced during TMEV encephalitis scaled with the amount of infectious virus in the initial inoculum. Cognitive performance was preserved in mice inoculated with 1.25 × 10⁴ PFU TMEV relative to 2 × 10⁵ PFU TMEV, but peak viral load at 72 hpi was equivalent between the inocula. CCL2 production in the brain was attenuated by 90% and TNFα and IL6 production was absent in mice inoculated with 1.25 × 10⁴ PFU TMEV. Acute infiltration of inflammatory monocytes was attenuated by more than 80% in mice inoculated with 1.25 × 10⁴ PFU TMEV relative to 2 × 10⁵ PFU TMEV but microglial activation was equivalent between groups. Seizure burden was attenuated and the threshold to kainic acid-induced seizures was higher in mice inoculated with 1.25 × 10⁴ PFU TMEV but low-level behavioral seizures persisted and the EEG exhibited reduced but detectable abnormalities.

Conclusions

The size of the inflammatory monocyte response induced by TMEV scales with the amount of infectious virus in the initial inoculum, despite the development of equivalent peak infectious viral load. In contrast, the microglial response does not scale with the inoculum, as microglial hyper-ramification and increased Iba-1 expression were evident in mice inoculated with either 1.25 × 10⁴ or 2 × 10⁵ PFU TMEV. Inoculation conditions that drive inflammatory monocyte infiltration resulted in robust behavioral seizures and EEG abnormalities, but the low inoculum condition, associated with only microglial activation, drove a more subtle seizure and EEG phenotype.

SUBMITTER: Howe CL

PROVIDER: S-EPMC8800194 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BACKGROUND:Muscle weakness is associated with increased mortality risk in chronic haemodialysis (CHD) patients. Protein energy wasting (PEW) and low physical activity could impair muscle quality and contribute to muscle weakness beyond muscle wasting in these patients. Aim of this study was to assess clinical and biological parameters involved in the reduction of muscle strength of CHD patients. METHODS:One hundred and twenty-three CHD patients (80 males, 43 females; 68,8 [57.9-78.8] y.o.) were included in this study. Maximal voluntary force (MVF) of quadriceps was assessed using a belt-stabilized hand-held dynamometer. Muscle quality was evaluated by muscle specific torque, defined as the strength per unit of muscle mass. Muscle mass was estimated using lean tissue index (LTI), skeletal muscle mass (SMM) assessed by bioelectrical impedance analysis and creatinine index (CI). Voorrips questionnaire was used to estimate physical activity. Criteria for the diagnosis of PEW were serum albumin, body mass index < 23 kg/m2, creatinine index < 18.82 mg/kg/d and low dietary protein intake estimated by nPCR < 0.80g/kg/d. RESULTS:MVF was 76.1 [58.2-111.7] N.m. and was associated with CI (? = 5.3 [2.2-8.4], p = 0.001), LTI (? = 2.8 [0.6-5.1], p = 0.013), Voorrips score (? = 17.4 [2.9-31.9], p = 0.02) and serum albumin (? = 1.9 [0.5-3.2], p = 0.006). Only serum albumin (? = 0.09 [0.03-0.15], p = 0.003), Voorrips score (? = 0.8 [0.2-1.5], p = 0.005) and CI (? = 0.2 [0.1-0.3], p<0.001) remained associated with muscle specific torque. Thirty patients have dynapenia defined as impaired MVF with maintained SMM and were younger with high hs-CRP (p = 0.001), PEW criteria (p<0.001) and low Voorrips score (p = 0.001), and reduced dialysis vintage (p<0.046). CONCLUSIONS:Beyond atrophy, physical inactivity and PEW conspire to impair muscle strength and specific torque in CHD patients and could be related to muscle quality. TRIAL REGISTRATION:ClinicalTrials.gov NCT02806089.