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.

Recommends

Please login to recommend the paper.

Comments

  1. 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.

    View all comments by Andy Tsai

  2. 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.

    View all comments by Julia TCW

  3. 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.

    View all comments by Na Wang

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Could Targeting CD22 Restore Microglial Lysosome Trafficking?