Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Deficiency Attenuates Phagocytic Activities of Microglia and Exacerbates Ischemic Damage in Experimental Stroke

Abstract

Clearing cellular debris after brain injury represents an important mechanism in regaining tissue homeostasis and promoting functional recovery. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified receptor expressed on microglia and is thought to phagocytose damaged brain cells. The precise role of TREM2 during ischemic stroke has not been fully understood. We explore TREM2 in both in vitro and in vivo stroke models and identify a potential endogenous TREM2 ligand. TREM2 knockdown in microglia reduced microglial activation to an amoeboid phenotype and decreased the phagocytosis of injured neurons. Phagocytosis and infarcted brain tissue resorption was reduced in TREM2 knock-out (KO) mice compared with wild-type (WT) mice. TREM2 KO mice also had worsened neurological recovery and decreased viable brain tissue in the ipsilateral hemisphere. The numbers of activated microglia and phagocytes in TREM2 KO mice were decreased compared with WT mice, and foamy macrophages were nearly absent in the TREM2 KO mice. Postischemia, TREM2 was highly expressed on microglia and TREM2-Fc fusion protein (used as a probe to identify potential TREM2 binding partners) bound to an unknown TREM2 ligand that colocalized to neurons. Oxygen glucose deprivation-exposed neuronal media, or cellular fractions containing nuclei or purified DNA, but not cytosolic fractions, stimulated signaling through TREM2. TREM2-Fc fusion protein pulled down nucleic acids from ischemic brain lysate. These findings establish the relevance of TREM2 in the phagocytosis of the infarcted brain and emphasize its role in influencing neurological outcomes following stroke. Further, nucleic acids may be one potential ligand of TREM2 in brain ischemia.

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

“…6). In keeping with our macroscopic observation that infarct areas in PAP‐1‐treated mice are shrunken on day‐8 after reperfusion MCAO and not swollen like in mice where phagocytosis is impaired (e.g., TREM2 −/− mice29), PAP‐1 treatment at both the low and the high dose did not reduce the percentage of CD68 + phagocytes closely contacting TUNEL + cells or containing TUNEL + material on day‐8. However, in animals treated with the higher dose of PAP‐1, overall fewer CD68 + phagocytes and less TUNEL + staining was observed (not shown), but the percentage of association/internalization was not significantly changed (Fig.…”

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

“…It has previously been reported that TREM2 is capable of binding microbial and damage-associated molecular signatures found on bacteria (41,42), lipids exposed during axonal injury (23,43), and nucleic acid released from dying cells (29). Here, we report apoE as a novel TREM2 ligand.…”

“…Overexpression of microglial TREM2, however, suppressed this excessive cytokine production under the same stimulatory conditions (27). Furthermore, TREM2 deficiency has been shown to result in reduced phagocytic activity of apoptotic neurons (24,28,29), A␤ (50,51), and E. coli (51) by microglia. A recent report elegantly demonstrated a direct role for TREM2 in facilitating phagocytosis both in vitro and in vivo.…”

“…This, in turn, recruits Syk via Src homology domain 2 and subsequent activation of downstream targets. Although the exact signaling mechanisms are unknown, studies utilizing TREM2-deficint mice and cells have shown that TREM2 is able to modulate key aspects of cellular homeostasis by suppressing inflammatory cytokine production (23)(24)(25)(26)(27) and facilitating phagocytosis of apoptotic cells (24,28,29). Within the periphery, TREM2 is found on the surface of osteoclasts, immature dendritic cells, and macrophages.…”

Third European Stroke Science Workshop

“…Yenari et al found decreased phagocytosis and infarcted brain tissue resorption in triggering receptor expressed by myeloid cells 2-deficient mice compared with wild-type mice subjected to experimental stroke. 9 Triggering receptor expressed by myeloid cells 2 further seems to be essential for neurological recovery in a stroke model.…”