TREM2 expression in the human brain: a marker of monocyte recruitment?

Abstract

Mutation in the triggering receptor expressed on myeloid cells (TREM) 2 gene has been identified as a risk factor for several neurodegenerative diseases including Alzheimer's disease (AD). Experimental studies using animal models of AD have highlighted a number of functions associated with TREM2 and its expression by microglial cells. It has therefore been assumed that this is also the case in humans. However, there is very limited information concerning the cellular expression of TREM2 in the human brain. As part of investigations of microglia using post-mortem resources provided by the Medical Research Council Cognitive Function and Ageing Studies (MRC-CFAS), we immunostained the cerebral cortex of 299 participants for TREM2 using the Sigma antibody HPA010917 and compared with the macrophage/microglial markers Iba1 and CD68. As expected, Iba1 and CD68 labeled microglia and perivascular macrophages. However, in most cases (284/299), the TREM2 antibody labelled monocytes within vascular lumens, but not microglia or perivascular macrophages. In contrast, in 5 out of 6 cases with acute infarcts, TREM2 immunoreaction identified cells within the brain parenchyma interpreted as recruited monocytes. Six cases with old infarcts contained phagocytic foamy macrophages which were CD68-positive but TREM2 negative. Our observations, using the HPA010917 anti-TREM2 antibody, suggest that TREM2 is not expressed by microglia but instead seems to be a marker of recruited monocytes in the human brain. This finding has implications with regards to the role of TREM2 as a risk factor, emphasizing the importance of systemic immune responses in the development and progression of Alzheimer's disease.

Keywords: TREM2; dementia; human brain; microglia; monocyte; neuropathology.

Figure 1

TREM2 immunostaining in spleen with (A) the anti‐TREM2 antibody HPA010917 from Sigma and with (B) the anti‐TREM2 AF1828 from R&D. Hematoxylin counterstaining, scale bar = 50 μm.

Figure 2

Iba1 and TREM2 immunolabeling. (A) Iba1 staining recognizes ramified microglia and perivascular macrophages; whereas (B) TREM2 staining in the same area detects only intravascular monocytes (*) but not microglia or perivascular macrophages (uninfarcted area). Acute infarct showing (C) high expression Iba1 in microglia and perivascular macrophages and (D) TREM2‐positive parenchymal cells within the infarct. The surrounding uninfarcted area contains Iba1‐positive (C) TREM2‐negative microglia (D)(*). The extravascular TREM2‐positive cells in the infarcted parenchyma have similar morphology to the TREM2‐positive intravascular monocytes and likely represent recruitment of circulating monocytes to the infarcted tissue. Hematoxylin counterstaining, scale bar (A, B) = 50 μm, (C, D) = 100 μm.

Figure 3

TREM2 and CD68 immunostaining in infarcts at different stages of evolution. (A–C) Uninfarcted region. (A) H&E staining showing preserved tissue. (B) TREM2 immunohistochemistry labelling of monocytes within the lumen of a blood vessel, but not microglia in the surrounding brain parenchyma. (C) CD68 immunohistochemistry showing staining of perivascular macrophages. (D–F) Acute cortical infarct with early neuropil disruption, neuronal ischemia and infiltration by neutrophils as observed on (D) H&E staining. (E) TREM2 immunohistochemistry showing numerous TREM2 labelled cells infiltrating the acutely infarcted cortex and present within vascular lumens. The cells have the morphology of monocytes rather than foamy macrophages or process‐bearing microglia. (F) CD68 immunohistochemistry showing no significant labelling of cells indicating the infarct is so acute that no phagocytosis of cell debris by macrophage/microglia has begun. (G) H&E staining showing an old cortical infarct with extensive neuropil disintegration and abundant foamy macrophages. (H) TREM2 immunohistochemistry showing the foamy macrophages are not labelled. A single monocyte is labelled within the lumen of a capillary within the infarct (inset top right). (I) CD68 immunohistochemistry showing immunoreactivity of abundant foamy macrophages. Counterstaining with Hematoxylin and eosin (H&E) for (A, D, G) and with Hematoxylin for (B, C, E, F, H, I); scale bar = 50 μm.