Hou J, Chen Y, Cai Z, Heo GS, Yuede CM, Wang Z, Lin K, Saadi F, Trsan T, Nguyen AT, Constantopoulos E, Larsen RA, Zhu Y, Wagner ND, McLaughlin N, Kuang XC, Barrow AD, Li D, Zhou Y, Wang S, Gilfillan S, Gross ML, Brioschi S, Liu Y, Holtzman DM, Colonna M. Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model. Sci Transl Med. 2024 Apr 3;16(741):eadj9052. PubMed.
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VIB-Center for Molecular Neurology
This is very interesting work, as it dives into the plethora of receptors that control microglial function. For very good reasons, the field has focused extensively on some specific molecules, such as TREM2 or CD33, but microglia express a vast diversity of activation (ITAMs) and inhibitory (ITIMs) receptors. The functional output of microglia will be the result of a complex computing of the integrated signal through all these receptors. In this manuscript, the authors focus on LILRB4, which is considered an inhibitory receptor.
The humanization strategy of the LILRB4 receptor is very elegant and adds stronger translational value to the work. There are some intriguing pieces of data, especially regarding the impact of the anti-LILRB4 treatment. The histopathological analysis shows increased accumulation of microglia around amyloid plaques upon treatment. However, the differential expression analysis shows a significant reduction in disease-associated microglia (DAM) genes such as Cd9, Alx, and Cd63. Could the treatment elicit a specific subtype of DAMs with protective function? Could this indicate that DAMs are more complex than we think, and that different subsets will engage in different functions? This could potentially open new and very exciting avenues of research.
Like every good paper, this thought-provoking piece of work leaves many questions. Is ApoE the only endogenous ligand of LILRB4? What is the nature of the protective microglia subtype elicited by the treatment? How does it compare with those that arise after TREM2 activation of anti-Ab immunotherapy?
View all comments by Renzo MancusoUC Davis
Microglia with unique transcriptional signatures have been identified in Alzheimer’s disease patients and animal models (Keren-Shaul et al., 2017). Understanding the regulation and impact of these states is essential if we want to know how to modulate microglia for therapeutic purposes. Transcription factors are starting to emerge (Gosselin et al., 2017) and are necessary for understanding the regulation of these complex transcriptional states. However, cell surface receptors such as TREM2, CD33, and here, LILRB4 are particularly appropriate for therapeutic approaches.
In this manuscript by Hou, Chen et al., the authors describe LILRB4 as a modulator of microglia. They evaluate the impact of LILRB4 on transcriptional states, microglia phagocytosis, and its overall impact on amyloid pathology. The development and characterization of an antibody that crosses the blood-brain barrier is critical here, and well done. This study also highlights the importance of developing the right tools to broadly understand microglia in disease; targeting human genes and assessing their impact on microglia transcription and function.
One caveat the authors highlight is the use of male amyloidosis mice only. While they emphasize the importance of testing it in models that recapitulate other hallmarks of diseases, such as tau and cerebral amyloid angiopathy, and in male and female animals, I would also emphasize the importance of testing LILRB4 in xenograft models. It is now possible to evaluate the impact on human iPSC-derived microglia transplanted in the mouse brain (Mancuso et al., 2019; Hasselmann et al., 2019) which would confirm the findings in human microglia. Overall, the authors define a very clear path for the identification and validation of new regulators of microglia states that could be highly promising therapeutically.
References:
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.
Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JC, Sajti E, Jaeger BN, O'Connor C, Fitzpatrick C, Pasillas MP, Pena M, Adair A, Gonda DD, Levy ML, Ransohoff RM, Gage FH, Glass CK. An environment-dependent transcriptional network specifies human microglia identity. Science. 2017 Jun 23;356(6344) Epub 2017 May 25 PubMed.
Mancuso R, Van Den Daele J, Fattorelli N, Wolfs L, Balusu S, Burton O, Liston A, Sierksma A, Fourne Y, Poovathingal S, Arranz-Mendiguren A, Sala Frigerio C, Claes C, Serneels L, Theys T, Perry VH, Verfaillie C, Fiers M, De Strooper B. Stem-cell-derived human microglia transplanted in mouse brain to study human disease. Nat Neurosci. 2019 Dec;22(12):2111-2116. Epub 2019 Oct 28 PubMed.
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View all comments by Martine TherrienUniversity College London
This is an exciting study by Hou and colleagues showing that modulating LILRB4 using an antibody likely inhibits LILRB4 binding to APOE, activating microglia and attenuating Aβ-related measures, such as plaque load and neuronal dystrophy. This study follows on from important earlier work by Kim and colleagues (2013) and Zhao and colleagues (2022) showing that the related inhibitory receptor LILRB2 binds Aβ. Additionally, with Valentina Escott-Price we showed gene variation in LILRB4 associated with Alzheimer’s disease risk (2019), and Bellenguez and colleagues identified variation for LILRB2 associated with dementia (2022).
This study by Hou et al. is thorough, well-powered, and well-reasoned. In future work, it would be good to explore which sub-population, or state of microglia, express LILRB4, as would be seen by single-cell RNA-Seq, and whether these are homeostatic, amyloid-responsive, disease-associated microglia, or interferon-responsive. It would be useful to know how the anti-LILRB4 antibody shifts microglia between different states. The data showing a positive association of the anti-LILRB4 antibody with phagocytic pathways, and a negative association with interferon pathways is interesting.
The authors showed P35, T30, and Y121 residues of LILRB4 contributed to APOE binding. In future work it would be good to see how LILRB4 carrying mutations of these residues affect Aβ load in mice—one would hypothesize reduced Aβ load—then test anti-LILRB4 antibodies in these animals. Investigating which residues this anti-LILRB4 ZM3.1 antibody, and other related antibodies, bind alongside APOE, may help increase clinical utility. Furthermore, it would be useful to understand if the anti-LILRB4 antibody mediates changes in Aβ pathology’s impact upon tau.
This careful study opens new opportunities to modulate microglial activity in Alzheimer’s disease.
References:
Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, Shatz CJ. Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science. 2013 Sep 20;341(6152):1399-404. PubMed.
Zhao P, Xu Y, Jiang LL, Fan X, Ku Z, Li L, Liu X, Deng M, Arase H, Zhu JJ, Huang TY, Zhao Y, Zhang C, Xu H, Tong Q, Zhang N, An Z. LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions. Mol Neurodegener. 2022 Jun 18;17(1):44. PubMed.
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