Effect of Toll-like receptor 2 activation on mitochondrial

Abstract

Effect of Toll-like receptor 2 activation on mitochondrial respiration and hypoxic-ischemic injury in the developing brain Student: Carl-Johan Mohn Supervisors: Carina Mallard, Amin Mottahedin, Joakim Ek ABSTRACT Introduction: Toll Like Receptors (TLR) are pathogen recognition receptors (PRRs), which play major roles in recognition and provoking inflammatory responses upon activation by pathogens such as bacteria, viruses and fungi. TLR2 is activated by binding to Pathogen associated molecular patterns (PAMPs) such as Lipoteichoic acid (LTA) and Lipoarabinomannan (LAM), which are found in Gram-positive bacteria respective Mycoplasma. As well as infections, Hypoxic-Ischemic (HI) events are a known risk factors for developing neonatal brain injury. Neonatal brain injury can result in conditions like Cerebral palsy, learning difficulties and even death. Aim of the study: The pathology behind neonatal brain injury is still not fully understood. By studying some specific cellular mechanisms such as cellular respiration, myelinisation, development of neurons and microglia in a Toll like receptor dependent manner, we could contribute to the understanding of this complex issue. Methods: TLR2 -/- mice and TLR2+/+ mice were injected intraperitoneally (ip.) with a TLR2 ligand (P3C) or saline 14h before exposed to Hypoxia-Ischemia (HI). The HI procedure were executed by ligating one of the common carotid arteries followed by putting the pups in an Oxygen deficient chamber for 50min. Brains were collected and stained immunohistochemically using different antibodies for neurons (MAP2), myelinisation (MBP) and Microglia (Iba1). Evaluation of the cellular respiration were made by using a high-resolution respirometer. Results: Here we present data to show that systemic activation of TLR2, with a synthetic ligand, increases subsequent HI brain injury in neonatal mice as demonstrated by increased neural tissue loss as well as reduced myelination. Using high-resolution respirometry, we show that systemic activation of TLR2 suppresses respiration in brain-isolated mitochondria. Conclusion: The results suggest that infection and inflammation might exacerbate hypoxicischemic injury through mitochondrial energy failure.