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Lactosylceramide-enriched microdomains mediate human neutrophil immunological functions via carbohydrate-carbohydrate interaction

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Abstract

The innate immune system of mammalian cells is the first line of defense against pathogenic microorganisms. Phagocytes, which play the central role in this system, engulf microorganisms by a mechanism that involves pattern recognition receptors on their own surface and pathogen-associated molecular patterns (PAMPs) expressed by the microorganism. Components of PAMPs include glycans (polysaccharides) and glycoconjugates (carbohydrates covalently linked to other biological molecules). Pathogenic microorganisms display specific binding affinity to various types of glycosphingolipids (sphingosine-containing glycolipids; GSLs), and GSLs are involved in host–pathogen interactions. We observed that lactosylceramide (LacCer), a neutral GSL, binds directly to certain pathogen-specific molecules (e.g., Candida albicans-derived β-glucans, mycobacterial lipoarabinomannan) via carbohydrate-carbohydrate interaction. LacCer is expressed highly on human neutrophils, and forms membrane microdomains. Such LacCer-enriched microdomains mediate several important neutrophil functions, including chemotaxis, phagocytosis, and superoxide generation. Human neutrophils phagocytose pathogenic mycobacteria (including Mycobacterium tuberculosis) through carbohydrate-carbohydrate interaction between LacCer on their own surface and mannose-capped lipoarabinomannan on the bacterium. During recognition of pathogen-specific glycans, direct association of LacCer-containing C24 fatty acid chain with Lyn (a Src family kinase) is necessary for signal transduction from the neutrophil exterior to interior. Pathogenic mycobacteria utilize a similar interaction to avoid killing by neutrophils. We describe here the mechanisms whereby LacCer mediates neutrophil immune systems via carbohydrate-carbohydrate interaction.

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Acknowledgements

Our research studies mentioned in this review were initiated and encouraged by Dr. Sen-itiroh Hakomori (The Biomembrane Institute and Dept. of Pathobiology, University of Washington, Seattle, WA, USA), for which we are highly appreciative. Our recent studies were supported in part by grants from Foundation of Strategic Research Projects in Private Universities (S1311011) and AMED under Grant Numbers 21gm0910006h0106 and 20ae0101068h0005 (to K.I.); JSPS KAKENHI under Grant Numbers JP17K10031, JP21K06086 (to H.N.) and JP20K17471 (to K.H.). We are grateful to Dr. S. Anderson for English editing of the manuscript.

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  1. Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka Urayasu, Chiba, 279-0021, Japan

    Kazuhisa Iwabuchi, Hitoshi Nakayama & Kei Hanafusa

  2. Infection Control Nursing, Juntendo University Graduate School of Health Care and Nursing, 2-5-1 Takasu Urayasu, Chiba, 279-0023, Japan

    Kazuhisa Iwabuchi & Hitoshi Nakayama

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Iwabuchi, K., Nakayama, H. & Hanafusa, K. Lactosylceramide-enriched microdomains mediate human neutrophil immunological functions via carbohydrate-carbohydrate interaction. Glycoconj J 39, 239–246 (2022). https://doi.org/10.1007/s10719-022-10060-0

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