Soluble Trem2 is a negative regulator of erythrophagocytosis after intracerebral hemorrhage in a CD36 receptor recycling manner.

sTrem2 reshapes the ICH-associated microglia/macrophages impairing erythrophagocytosis and enhancing inflammation via inhibition of Vps35-mediated pro-erythrophagocytic molecular receptor CD36 recycling and lysosomal degradation of unrecycled CD36, causing exacerbation of neuronal loss and neurological dysfunction after ICH. [Display omitted] • Soluble Trem2 delays the microglia/macrophages mediated hematoma resolution after ICH • Soluble Trem2 modulates erythrophagocytosis in a full-length Trem2 independent pathway. • Soluble Trem2 inhibits CD36 receptor recycling and exacerbates lysosomal degradation of unrecycled CD36 in microglia/macrophages. Microglia and macrophages participate in hematoma clearance after intracerebral hemorrhage (ICH), thereby facilitating tissue restoration and neurological recovery. Triggering receptor expressed on myeloid cells 2 (Trem2) has been indicated as a major pathology-induced immune signaling hub on the microglial/macrophage surface. Soluble Trem2 (sTrem2), the proteolytic form of Trem2, is abundant in the body fluid and is positively correlated with the pathological process. In the present study, we aimed to investigate the potential role of sTrem2 in hematoma resolution after ICH and to elucidate its underlying mechanisms. We explored the biological functions of sTrem2 in the murine ICH brain by stereotaxic injection of recombinant sTrem2 protein or by adeno-associated virus-mediated expression. Erythrocyte phagocytosis was assessed using flow cytometry and immunofluorescence. Western blotting was performed to evaluate protein expression. Changes in behavior, sTrem2-induced down-stream pathway, and microglia were examined. sTrem2 impedes hematoma resolution and impairs functional motor and sensory recovery. Interestingly, sTrem2 bypasses full-length Trem2, negatively regulating microglial/macrophage erythrophagocytosis, and promotes an inflammatory phenotype, which is associated with reduced retromer levels and impaired recycling of the pro-erythrophagocytic receptor CD36. Rescue of retromer Vps35 abolishes the phagocytosis-inhibiting effects and lysosome-dependent CD36 degradation caused by sTrem2. These findings indicate sTrem2 as a negative factor against microglia/macrophage-mediated hematoma and related neuronal damage clearance, provide insight into the mechanisms by which erythrophagocytosis is regulated and how it may be impaired after ICH, and suggest that the anti-proteolytic activity of Trem2 can be explored for ICH therapy. [ABSTRACT FROM AUTHOR]