. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med. 2017 Mar 6;214(3):597-607. Epub 2017 Feb 16 PubMed.

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  1. Zhong et al. report that soluble forms of TREM2 are able to elicit a robust proinflammatory response and promote survival in primary microglia. These findings provide a completely novel take on the biological roles of soluble TREM2. Previous work has shown, using a similar sTREM2-Fc fusion protein, that soluble Trem2 disrupts Trem2 signaling involved in osteoclastogenesis (Kim et al., 2005). Since then, the field’s focus has shifted to the use of sTREM2 as a clinical biomarker for AD and other neurodegenerative diseases (Piccio et al., 2008; Piccio et al., 2016; Heslegrave et al., 2016; Suarez-Calvet et al., 2016). A homologous soluble factor, soluble Trem1 was demonstrated to reverse LPS-induced endotoxic shock by reducing proinflammatory cytokine levels and promoting survival  of mice injected with murine Trem1-Fc fusion protein systemically (Bouchon et al., 2001). These findings, in light of the Zhong et al. paper, illustrate that soluble TREM proteins do modulate inflammation and survival mechanisms.

    Zhong and colleagues show that sTREM2 acts in an autocrine manner to drive the expression of NFκB-dependent proinflammatory cytokine expression and microglial survival. These effects are independent of the endogenous microglial TREM2 receptor and its adapter DAP12. The central question arising from these findings is how the cleaved TREM2 extracellular domain interacts with primary microglia to elicit activation of the intracellular signaling cascades. Immunohistochemistry depicts a change in microglial phenotype characteristic of activation with both in vitro and in vivo application of sTREM2-Fc. Conceptually, these data support recent proposals that the presence of sTREM2, as detected in human biological samples, indicates microglial activation (Ohrfelt et al., 2016; Gispert et al., 2016a; Gispert et al., 2016Suarez-Calvet et al., 2016Heslegrave et al., 2016Piccio et al., 2016). This new study begins to address the significance of sTREM2 release on microglial function and the overall innate immune response in the context of disease. A major caveat with previous studies employing sTREM2-Fc fusion protein to assess Trem2 function is that this chimeric protein may not mimic the physiological activity of Trem2 and its soluble form. This study is the first to validate their findings with sTREM2-Fc using an untagged form of sTREM2.

    The primary data describe a very robust induction of IL-1β, IL-6 and TNFα mRNA levels within four hours following exposure to sTREM2. In the case of IL-6, mRNA levels rose more than 3,000 fold and IL-1β 120-fold, a response that is greater than that typically elicited by TLR4 stimulation and was highly variable between assays. However, protein levels were not quantitated and only normalized RNA values were provided.

    One of the key findings of the study was the observation that disease-linked sTREM2 variants were about 50 percent less effective in suppressing apoptosis of microglia deprived of GM-CSF and of stimulating cytokine mRNA levels similar to WT sTREM2-Fc. Others have shown the particular variants tested, R47H and R62H, as either Trem2-Fc proteins (Yeh et al., 2016) or expressed within reporter cell lines (Song et al., 2016) to impede Trem2 recognition of apolipoproteins. Thus, these variants appear to impair ligand binding, which could explain the findings by Zhong et al. examining these variants when expressed in sTREM2-Fc constructs.

    Unanswered is the question of whether sTREM2 has analogous deleterious effects on astrocytes and neurons, and what relationship sTREM2 has with full-length Trem2. Trem2 has historically been described as anti-inflammatory, but many studies now depict Trem2 as an amplifier of inflammatory responses under multiple contexts, including traumatic brain injury (Saber et al., 2017), ischemia (Sieber et al., 2013), and demyelination (Poliani et al., 2015). Some (Kleinberger et al., 2014; Piccio et al., 2008) have proposed sTREM2 to serve as a decoy receptor for full-length Trem2 that works antagonistically to Trem2, but this study shows for the first time that sTREM2 may complement and even amplify Trem2 signaling. 

    References:

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    . Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury. Sci Transl Med. 2016 Dec 14;8(369):369ra178. PubMed.

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    View all comments by Gary Landreth
  2. The article represents a potentially interesting finding regarding the role of sTREM2 in triggering microglial activation. Although it is known that there is an increase in sTREM2 in many disease states, the role that sTREM2 plays is still relatively unknown. The data presented here provide a first step toward this goal, suggesting a protective function of sTREM2 on microglia in steady state. There are, however, a few outstanding questions that I have outlined below.

    1. The authors do not identify a receptor, nor do they provide evidence regarding how sTREM2 may be exerting a protective effect.    

    2. The use of sTREM2-Fc is interesting and very valuable but is not overly physiological. Although the authors control for the Fc portion in many experiments it is unclear what effect tethering an Fc fragment may have on sTREM2. The authors do generate a TEV-Fc version of sTREM2, which can be cleaved resulting in a non-Fc version of sTREM2, but this “clean” sTREM2 was not used throughout the paper. 

    3. The in vivo experiment is a bit confusing. In WT mice there is likely to be some sTREM2 already available. It is difficult to understand why sTREM2-Fc has such a robust effect in WT mice and why sTREM2 generally elicits a very similar response in both WT and TREM2-/- mice. Again, these results would have been greatly strengthened if the authors had used their sTREM2 without an Fc.

    4. Finally, the most important question, which is what role does sTREM2 play in disease, remains to be addressed. I guess the authors will follow this up soon.

    View all comments by Marco Colonna

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