The surface-exposed chaperone Hsp60 is an agonist of the microglial TREM2 receptor.
 

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05-22-09 09:22 AM
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The surface-exposed chaperone Hsp60 is an agonist of the microglial TREM2 receptor.
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The surface-exposed chaperone Hsp60 is an agonist of the microglial TREM2 receptor.

J Neurochem. 2009 Apr 29;

Authors: Stefano L, Racchetti G, Bianco F, Passini N, Gupta RS, Bordignon PP, Meldolesi J

Abstract TREM, a receptor expressed by myeloid cells, osteoclasts and microglia, is known to play a protective role in bones and brain. Mutations of the receptor (or of its coupling protein, DAP12) sustain in fact a genetic disease affecting the two organs, the Polycystic Lipomembraneous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL or Nasu-Hakola disease). So far, specific agonist(s) of TREM2 have not been identified and its (their) transduction mechanisms are largely unknown. Hsp60 is a mitochondrial chaperone that can also be harboured at the cell surface. By using constructs including the extracellular domain of TREM2 and the Fc domain of IgGs we have identified Hsp60 as the only TREM2-binding protein exposed at the surface of neuroblastoma N2A cells and astrocytes, and lacking in U373 astrocytoma. Treatment with Hsp60 was found to stimulate the best known TREM2-dependent process, phagocytosis, however only in the microglial N9 cells, rich of the receptor. Upon TREM2 down-regulation the Hsp60-induced stimulation of N9 phagocytosis was greatly attenuated. Hsp60 is also released by many cell types, segregated within exosomes or shedding vesicles which might then undergo dissolution. However, the affinity of its binding (Kd 3.8 muM) might be too low for the soluble chaperone, released from the vesicles to the extracellular space, to induce a significant activation of TREM2. It might in contrast be appropriate for the binding of TREM2 to Hsp60 exposed at the surface of cells closely interacting with microglia. The ensuing stimulation of phagocytosis could play protective effects on the brain.

PMID: 19457124 [PubMed - as supplied by publisher]