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Zhong L, Chen XF, Wang T, Wang Z, Liao C, Wang Z, Huang R, Wang D, Li X, Wu L, Jia L, Zheng H, Painter M, Atagi Y, Liu CC, Zhang YW, Fryer JD, Xu H, Bu G. 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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Indiana University School of Medicine
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., 2016; Suarez-Calvet et al., 2016; Heslegrave et al., 2016; Piccio 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:
Kim Y, Sato K, Asagiri M, Morita I, Soma K, Takayanagi H. Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis. J Biol Chem. 2005 Sep 23;280(38):32905-13. Epub 2005 Jul 26 PubMed.
Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.
Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, Rinker J 2nd, Naismith RT, Panina-Bordignon P, Passini N, Galimberti D, Scarpini E, Colonna M, Cross AH. Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain. 2008 Nov;131(Pt 11):3081-91. Epub 2008 Sep 12 PubMed.
Heslegrave A, Heywood W, Paterson R, Magdalinou N, Svensson J, Johansson P, Öhrfelt A, Blennow K, Hardy J, Schott J, Mills K, Zetterberg H. Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer's disease. Mol Neurodegener. 2016 Jan 12;11:3. PubMed.
Suárez-Calvet M, Araque Caballero MÁ, Kleinberger G, Bateman RJ, Fagan AM, Morris JC, Levin J, Danek A, Ewers M, Haass C, Dominantly Inherited Alzheimer Network. 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.
Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 2001 Apr 26;410(6832):1103-7. PubMed.
Öhrfelt A, Axelsson M, Malmeström C, Novakova L, Heslegrave A, Blennow K, Lycke J, Zetterberg H. Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Mult Scler. 2016 Jan 11; PubMed.
Gispert JD, Suárez-Calvet M, Monté GC, Tucholka A, Falcon C, Rojas S, Rami L, Sánchez-Valle R, Lladó A, Kleinberger G, Haass C, Molinuevo JL. Cerebrospinal fluid sTREM2 levels are associated with gray matter volume increases and reduced diffusivity in early Alzheimer's disease. Alzheimers Dement. 2016 Dec;12(12):1259-1272. Epub 2016 Jul 14 PubMed.
Gispert JD, Monté GC, Suárez-Calvet M, Falcon C, Tucholka A, Rojas S, Rami L, Sánchez-Valle R, Lladó A, Kleinberger G, Haass C, Molinuevo JL. The APOE ε4 genotype modulates CSF YKL-40 levels and their structural brain correlates in the continuum of Alzheimer's disease but not those of sTREM2. Alzheimers Dement (Amst). 2017;6:50-59. Epub 2016 Dec 22 PubMed.
Suárez-Calvet M, Araque Caballero MÁ, Kleinberger G, Bateman RJ, Fagan AM, Morris JC, Levin J, Danek A, Ewers M, Haass C, Dominantly Inherited Alzheimer Network. 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.
Heslegrave A, Heywood W, Paterson R, Magdalinou N, Svensson J, Johansson P, Öhrfelt A, Blennow K, Hardy J, Schott J, Mills K, Zetterberg H. Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer's disease. Mol Neurodegener. 2016 Jan 12;11:3. PubMed.
Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.
Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M. TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 2016 Jul 20;91(2):328-40. PubMed.
Song W, Hooli B, Mullin K, Jin SC, Cella M, Ulland TK, Wang Y, Tanzi RE, Colonna M. Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 2017 Apr;13(4):381-387. Epub 2016 Aug 9 PubMed.
Saber M, Kokiko-Cochran O, Puntambekar SS, Lathia JD, Lamb BT. Triggering Receptor Expressed on Myeloid Cells 2 Deficiency Alters Acute Macrophage Distribution and Improves Recovery after Traumatic Brain Injury. J Neurotrauma. 2016 May 9; PubMed.
Sieber MW, Jaenisch N, Brehm M, Guenther M, Linnartz-Gerlach B, Neumann H, Witte OW, Frahm C. Attenuated inflammatory response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice following stroke. PLoS One. 2013;8(1):e52982. Epub 2013 Jan 3 PubMed.
Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, Colonna M. TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest. 2015 May;125(5):2161-70. Epub 2015 Apr 20 PubMed.
Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, Rinker J 2nd, Naismith RT, Panina-Bordignon P, Passini N, Galimberti D, Scarpini E, Colonna M, Cross AH. Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain. 2008 Nov;131(Pt 11):3081-91. Epub 2008 Sep 12 PubMed.
View all comments by Gary LandrethWashington University School of Medicine
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.
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