Triggering receptor expressed on myeloid cells 2 deficiency exacerbates injury-induced inflammation in a mouse model of tauopathy.

Abstract

Traumatic brain injury (TBI) promotes several Alzheimer's disease-like pathological features, including microtubule-associated protein tau (MAPT) accumulation within neurons. Macrophage activation in the injured hTau mouse model of tauopathy raises the question whether there is a relationship between MAPT pathology and alterations in macrophage activation following TBI. Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical regulator of microglia and macrophage phenotype, but its mechanisms on TBI remain unclear. To address the association with TREM2 in TBI and MAPT pathology, we studied TREM2 deficiency in hTau mice (hTau;Trem2-/- ) 3 (acute phase) and 120 (chronic phase) days after experimental TBI. At three days following injury, hTau;Trem2-/- mice exhibited reduced macrophage activation both in the cortex and hippocampus. However, to our surprise, hTau;Trem2-/- mice exposed to TBI augments macrophage accumulation in the corpus callosum and white matter near the site of tissue damage in a chronic phase, which results in exacerbated axonal injury, tau aggregation, and impaired neurogenesis. We further demonstrate that TREM2 deficiency in hTau injured mice promotes neuronal dystrophy in the white matter due to impaired phagocytosis of apoptotic cells. Remarkably, hTau;Trem2-/- exposed to TBI failed to restore blood-brain barrier integrity. These findings imply that TREM2 deficiency accelerates inflammation and neurodegeneration, accompanied by attenuated microglial phagocytosis and continuous blood-brain barrier (BBB) leakage, thus exacerbating tauopathy in hTau TBI mice.

• Authors: Atsuko Katsumoto, Olga N Kokiko-Cochran, Shane M Bemiller, Guixiang Xu, Richard M Ransohoff, Bruce T Lamb
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 978423 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 36389767 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2022 Katsumoto, Kokiko-Cochran, Bemiller, Xu, Ransohoff and Lamb.

Chemical References

• Trem2 protein, mouse
• Membrane Glycoproteins
• Receptors, Immunologic

Topics

• Mice
• Animals
• Tauopathies (metabolism)
• Myeloid Cells (pathology)
• Microglia (metabolism)
• Disease Models, Animal
• Inflammation (metabolism)
• Brain Injuries, Traumatic (metabolism)
• Membrane Glycoproteins (genetics, metabolism)
• Receptors, Immunologic (genetics, metabolism)