Could Targeting CD22 Restore Microglial Lysosome Trafficking?
Quick Links
In many neurodegenerative disorders, microglia come down with a kind of indigestion, and no longer degrade lipids and other molecules. In the December 1 Science Translational Medicine, researchers led by Tony Wyss-Coray at Stanford University School of Medicine in Palo Alto, California, proposed a way to get these cells’ systems moving again. In microglia that carried a gene for the lysosomal storage disorder Niemann-Pick type C (NPC) disease, blocking the signaling molecule sCD22 restored lysosome function and lowered cholesterol accumulation. The researchers had previously shown a similar dynamic in mice, in which blocking CD22 stimulated microglial phagocytosis.
- In human brain, CD22 is expressed in oligodendrocytes, its receptor on microglia.
- Binding of sCD22 to IGFR2 scrambles lysosomal trafficking, and lipids build up.
- Blocking this binding restored lysosomal function.
Surprisingly, however, they found that in human brain, CD22 is made by oligodendrocytes, not microglia, and its soluble portion affects human microglia through a different mechanism. The findings emphasize, once again, differences between mouse and human biology. Still, they strengthen the case for targeting CD22 to treat NPC and possibly other neurodegenerative conditions.
Others were intrigued by the oligodendrocyte-microglia connection. “[This study] suggests oligodendrocytes modulate microglial function via receptor-ligand interactions,” Julia TCW at Boston University wrote to Alzforum. Gary Landreth and Andrew Tsai at Indiana University School of Medicine, Indianapolis, called the findings exciting. “This is a comprehensive and impressive study … the findings lend support to a novel therapeutic strategy of microglia-directed immunotherapeutics to treat Alzheimer’s disease,” they wrote (comments below).
Mouse versus Human. In-situ hybridization of human cortex finds CD22 transcripts (purple) only in human oligodendrocytes expressing myelin oligodendrocyte protein (green), not in microglia (IBA1, red), where CD22 is expressed in mice (not pictured). Nuclei are blue. [Courtesy of Science Translational Medicine/AAAS.]
In the previous study, Wyss-Coray and colleagues found that CD22, a Siglec and B-cell receptor that modulates adaptive immunity, was active in mouse microglia. Its microglial expression rose with age, blocked phagocytosis, but giving old mice an anti-CD22 antibody improved microglial consumption of aggregated proteins, myelin debris—and memory (Apr 2019 news).
Would this hold in human brain? As a first step, first author John Pluvinage, now at the University of California, San Francisco, examined an snRNA-Seq database of human cortex (Hodge et al., 2019). To his surprise, the data showed that only oligodendrocytes expressed CD22. Pluvinage confirmed this with in situ hybridization and flow cytometry of human cortex.
However, membrane-bound CD22 is not the whole story; the receptor can be clipped to release a soluble stub. Pluvinage found that microglia from postmortem human brain bound sCD22, suggesting they expressed a receptor for it.
To find the receptor, the researchers knocked out proteins in microglia-like cells derived from human iPSCs (iMGLs) and, lo and behold, deleting insulin-like growth factor 2 receptor (IGF2R) abolished sCD22 binding. Co-immunoprecipitation confirmed an interaction between the two proteins. Curiously, however, IGF2R is expressed by all brain cells, yet in tissue isolated from postmortem human brain, sCD22 clung only to microglia. Selectivity may be thanks to ST6GaL1, a co-receptor known to bind sCD22 and expressed only by microglia, the authors noted.
What does sCD22 binding do? In iMGLs, sCD22 sequestered IGF2R on the cell surface, depleting the receptor from late endosomes and lysosomes. Other lysosomal proteins such as cathepsin D and NPC1 also became scarce, hinting that vesicular IGF2R is necessary for proper lysosomal trafficking. Notably, sCD22 was previously linked to lysosomal disorders. People with NPC have large amounts of it in their cerebrospinal fluid.
To intervene in this system, the authors made an antibody, M42, that blocked sCD22 binding to IGR2R. Next, they developed a cell-culture model of NPC by treating iMGLs carrying an NPC1 mutation with sCD22-laden CSF from people with the disorder. The iMGLs accumulated large lysosomes choked with cholesterol. Treating the cells with M42 relieved this buildup. It also normalized gene expression, boosting genes involved in cholesterol metabolism and lowering stress-response genes. The results suggest that blocking sCD22 could be a strategy for improving microglial lipid metabolism, the authors note. This might be broadly applicable, as several recent studies have shown that glial lipid metabolism goes haywire in Alzheimer’s, and Parkinson’s disease is marked by lysosomal dysfunction (Dec 2019 news; Jan 2020 news; Nov 2021 conference news).
Why would an oligodendrocyte protein affect the metabolism of microglia? Pluvinage noted that oligodendrocyte-microglia crosstalk is common in development, aging, and neurodegeneration (Wlodarczyk et al., 2017; Safaiyan et al., 2021; Depp et al., 2021). During demyelination, sCD22 is likely released along with myelin fragments, he suggested. “We think the CD22-IGF2R interaction is an important line of communication between these two cell types,” Pluvinage wrote to Alzforum.
Na Wang at the Mayo Clinic in Jacksonville, Florida, noted that future work should decipher the structural characteristics of CD22-IGF2R binding and validate the findings in vivo (comment below). Pluvinage said this is next. “We are excited by the translational potential of blocking CD22 to treat NPC, and its applicability to other lysosomal storage and neurodegenerative diseases,” he wrote.—Madolyn Bowman Rogers
References
News Citations
- CD22 Suppresses Microglial Phagocytosis—A New Therapeutic Target?
- Lysosomal Diseases: Stepping Stones to Gene Therapy for Alzheimer’s?
- Does Young-Onset Parkinson’s Arise in Lysosomes?
- Do Lipids Lubricate ApoE's Part in Alzheimer Mechanisms?
Paper Citations
- Hodge RD, Bakken TE, Miller JA, Smith KA, Barkan ER, Graybuck LT, Close JL, Long B, Johansen N, Penn O, Yao Z, Eggermont J, Höllt T, Levi BP, Shehata SI, Aevermann B, Beller A, Bertagnolli D, Brouner K, Casper T, Cobbs C, Dalley R, Dee N, Ding SL, Ellenbogen RG, Fong O, Garren E, Goldy J, Gwinn RP, Hirschstein D, Keene CD, Keshk M, Ko AL, Lathia K, Mahfouz A, Maltzer Z, McGraw M, Nguyen TN, Nyhus J, Ojemann JG, Oldre A, Parry S, Reynolds S, Rimorin C, Shapovalova NV, Somasundaram S, Szafer A, Thomsen ER, Tieu M, Quon G, Scheuermann RH, Yuste R, Sunkin SM, Lelieveldt B, Feng D, Ng L, Bernard A, Hawrylycz M, Phillips JW, Tasic B, Zeng H, Jones AR, Koch C, Lein ES. Conserved cell types with divergent features in human versus mouse cortex. Nature. 2019 Sep;573(7772):61-68. Epub 2019 Aug 21 PubMed.
- Wlodarczyk A, Holtman IR, Krueger M, Yogev N, Bruttger J, Khorooshi R, Benmamar-Badel A, de Boer-Bergsma JJ, Martin NA, Karram K, Kramer I, Boddeke EW, Waisman A, Eggen BJ, Owens T. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 2017 Nov 15;36(22):3292-3308. Epub 2017 Sep 28 PubMed.
- Safaiyan S, Besson-Girard S, Kaya T, Cantuti-Castelvetri L, Liu L, Ji H, Schifferer M, Gouna G, Usifo F, Kannaiyan N, Fitzner D, Xiang X, Rossner MJ, Brendel M, Gokce O, Simons M. White matter aging drives microglial diversity. Neuron. 2021 Apr 7;109(7):1100-1117.e10. Epub 2021 Feb 18 PubMed.
- Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Steixner-Kumar AA, Subramanian S, Möbius W, Göbbels S, Saher G, Zampar S, Wirths O, Thalmann M, Saito T, Saido T, Krueger-Burg D, Kawaguchi R, Willem M, Haass C, Geschwind D, Ehrenreich H, Stassart R, Nave KA. Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer’s disease. bioRxiv. August 2, 2021
Further Reading
Primary Papers
- Pluvinage JV, Sun J, Claes C, Flynn RA, Haney MS, Iram T, Meng X, Lindemann R, Riley NM, Danhash E, Chadarevian JP, Tapp E, Gate D, Kondapavulur S, Cobos I, Chetty S, Pașca AM, Pașca SP, Berry-Kravis E, Bertozzi CR, Blurton-Jones M, Wyss-Coray T. The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C. Sci Transl Med. 2021 Dec;13(622):eabg2919. PubMed.
Annotate
To make an annotation you must Login or Register.
Comments
Indiana University School of Medicine
Stanford University
In this exciting new study, Wyss-Coray and colleagues report novel CNS actions of CD22, a well-studied B cell SIGLEC whose best-documented actions are to inhibit B cell receptor signaling. They originally identified CD22 in a screen for modifiers of microglial phagocytosis that are induced in aged microglia. Significantly, a soluble form of CD22 (sCD22) was found to be elevated in a rare progressive genetic disorder, Niemann-Pick type C, motivating a search for its origins.
In the course of this work, they uncovered a provocative difference between humans and mice in that CD22 was previously reported to be microglia-specific in mouse brain but is expressed by oligodendrocytes in the human brain. It is notable that humans have 14 protein transcripts of CD22, and mice have eight, raising the question of whether all of the sCD22 species are biologically active and how sCD22 actions differ between human and mouse. Nothing is known about how sCD22 is generated.
Importantly, the authors showed that IGF2R is a binding partner of sCD22 on myeloid cells by using genetic and proteomic screens. Given that IGFR2 is expressed by most cell types, it seems plausible that sCD22 might have more diverse functions. The most compelling observation in this study is the demonstration that disruption of the CD22-IGF2R interaction ameliorates lysosome dysfunction in human NPC1-mutant iPSC-derived microglia-like cells. The findings also lend support to a novel therapeutic strategy of microglia-directed immunotherapeutics to treat Alzheimer’s disease.
These data serve to reinforce that dysfunctional glial cells in the brain and their interaction play critical roles in protein aggregation, neuroinflammation, and disrupted lipid metabolism that relate to cognition, aging and dementia. It is curious that a classical immune receptor can moonlight in the CNS to influence myelination. Overall, this is a comprehensive and impressive study, elegantly done.
Boston University School of Medicine
Pluvinage et al. brought attention to Siglecs in brain function and neurodegeneration (Siddiqui et al., 2019). The Siglecs are mostly expressed in microglia regulating neuroinflammation, but some are present on oligodendrocytes involved in myelination. Siglec 2, CD22, is a receptor predominantly expressed in peripheral B cells; but in brain, Wyss-Coray and colleagues identified CD22 expression to be enriched in human oligodendrocytes, and its direct binding partner IGF2R in microglia. Interestingly, soluble CD22 potentially from oligodendrocytes causes lysosomal cholesterol accumulation in microglia of Niemann-Pick C, suggesting oligodendrocytes modulate microglial function via receptor-ligand interaction between different cell types. This study tells us that defects present in other cell types lead to disruption of microglial homeostasis in neurodegenerative diseases.
Lysosomal disruptions could be a general mechanism in neurodegenerative disease, but it is possible that sCD22 is enriched only in NPC but no other neurodegenerative diseases. APOE4 in AD shows similar disease phenotypes as NPC: decreased NPC1, accumulation of unesterified free cholesterol and lysosomal dysfunction in glia (TCW et al., 2019). In Parkinson's risk variants in GBA, which encodes a lysosomal enzyme implicated in lysosomal storage disorder, and in LRRK2 are involved in lysosomal degradation in glia (Tremblay et al., 2019). Different genetic risk variants or mutations can be converged on the same downstream functional defects, including lysosomal clearance, lipid accumulation, and inflammation.
Blocking sCD22 restored activated microglia to the homeostatic stage of lysosomes and lipid storage in NPC. Thus modulating Siglecs to reverse phenotypic defects could be a viable therapeutic target. While different Siglec-receptor interaction per different neurodegenerative disorders could be involved leading to, e.g., lysosomal disruption, identifying Siglecs enriched per different neurodegenerative disease, finding their binding partners and downstream functions, could be a valuable future approach.
References:
Siddiqui SS, Matar R, Merheb M, Hodeify R, Vazhappilly CG, Marton J, Shamsuddin SA, Al Zouabi H. Siglecs in Brain Function and Neurological Disorders. Cells. 2019 Sep 22;8(10) PubMed.
Tcw J, Qian L, Pipalia NH, Chao MJ, Liang SA, Shi Y, Jain BR, Bertelsen SE, Kapoor M, Marcora E, Sikora E, Andrews EJ, Martini AC, Karch CM, Head E, Holtzman DM, Zhang B, Wang M, Maxfield FR, Poon WW, Goate AM. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell. 2022 Jun 23;185(13):2213-2233.e25. PubMed. BioRxiv.
Tremblay ME, Cookson MR, Civiero L. Glial phagocytic clearance in Parkinson's disease. Mol Neurodegener. 2019 Apr 5;14(1):16. PubMed.
Mayo Clinic Florida
Phagocytosis is one of the most important functions of microglia, and lysosomes play essential roles in this process, hence studies on related pathways are critically important. Lysosome dysfunction has been reported in various age-related diseases like AD and PD, so this pathway could be a more general mechanism in neurodegeneration. However, the authors used different methods to prove an interaction between CD22 and the IGF2R, and high-resolution structural characterization of this interaction is lacking.
The interaction between oligodendrocytes and microglia attracts more and more attention. It is reported that oligodendrocytes may secrete factors that stimulate microglia to phagocytose damaged cells, thereby removing debris and aiding repair. Alternatively, stressed oligodendrocytes may trigger protective microglial pro-repair responses, for example by production of stress proteins such as αB-crystallin to reduce tissue damage. The results from this work suggest that oligodendrocytes can impair microglial lysosome protein trafficking function through a sCD22-IGF2R pathway, thereby disrupting microglial phagocytosis of apoptotic cells and toxic debris. This work supplies further evidence for the interaction of oligodendrocytes and microglia.
Based on the findings in this paper, I have concerns for blocking CD22 as a therapeutic strategy, for there are some limitations that the authors mention in the discussion. First, the work is not validated in vivo; second, a high-resolution structural characterization of sCD22- IGF2R interaction needs further study; third, the off-target effects. Moreover, an antibody- blocking therapeutic method may cause a side effect to the human system, even as the authors proved the safety of their CD22 mAb in vitro. The human system is complicated and very different from the in vitro state. Therefore, in vivo and further clinical experiments studies are needed.
Make a Comment
To make a comment you must login or register.