Professor Paul Crocker FRSE
Our research is aimed at understanding how immune cells utilise host glycans to regulate immune and inflammatory respones and translating this to human disease. All cells of the body are covered in a dense coating of glycans attached to proteins and lipids, some of which can act as ligands for lectin-like receptors expressed by cells of the innate and adaptive immune systems. We focus on the siglec family of sialic acid binding Ig-like lectins, many of which were discovered in my laboratory .
There are 15 siglecs in humans and 9 in mice, most of which are expressed in the immune system where they are thought to interact with host glycans to modulate immune and inflammatory responses. Our recent work has dissected in vivo functions of sialoadhesin (siglec-1/CD169) in (a) regulating autoimmune disease via interactions with activation-induced ligands on different T cell subsets and (b) promoting phagocytosis of the sialylated pathogen Campylobacter jejuni and triggering of MyD88-dependent cytokine and type I IFN responses . We have also recently discovered that murine siglec-E is an important negative regulator of beta2 integrin-dependent neutrophil inflammation in the lung.
Our current work is aimed at molecular dissection of the signalling pathways and identification of cis- and trans binding partners for siglecs involved in these biological functions.
Level 3 and Level 4 undergraduate lectures in Immunology.
4D01-Molecular Biology of Infection & Immunity
Nagala, M, McKenzie, E, Richards, H, Sharma, R, Thomson, S, Mastroeni, P & Crocker, P 2018, 'Expression of Siglec-E alters the phenotype of macrophages but does not affect LPS-driven cytokine production or TLR4 endocytosis' Frontiers in Immunology, vol. 8, 1926, pp. 1-17. https://doi.org/10.3389/fimmu.2017.01926
van Dinther, D, Veninga, H, Iborra, S, Borg, EGF, Hoogterp, L, Olesek, K, Beijer, MR, Schetters, STT, Kalay, H, Garcia-Vallejo, JJ, Franken, KL, Cham, LB, Lang, KS, van Kooyk, Y, Sancho, D, Crocker, PR & den Haan, JMM 2018, 'Functional CD169 on Macrophages Mediates Interaction with Dendritic Cells for CD8+ T Cell Cross-Priming' Cell Reports, vol. 22, no. 6, pp. 1484-1495. https://doi.org/10.1016/j.celrep.2018.01.021
Ercoli, G, Fernandes, VE, Chung, WY, Wanford, JJ, Thomson, S, Bayliss, CD, Straatman, K, Crocker, PR, Dennison, A, Martinez-Pomares, L, Andrew, PW, Moxon, ER & Oggioni, MR 2018, 'Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia' Nature Microbiology, vol. 3, pp. 600-610. https://doi.org/10.1038/s41564-018-0147-1
Shinde, PV, Xu, HC, Maney, SK, Kloetgen, A, Namineni, S, Zhuang, Y, Honke, N, Shaabani, N, Bellora, N, Doerrenberg, M, Trilling, M, Pozdeev, VI, van Rooijen, N, Scheu, S, Pfeffer, K, Crocker, PR, Tanaka, M, Duggimpudi, S, Knolle, P, Heikenwalder, M, Ruland, J, Mak, TW, Brenner, D, Pandyra, AA, Hoell, JI, Borkhardt, A, Häussinger, D, Lang, KS & Lang, PA 2018, 'Tumor Necrosis Factor-mediated survival of CD169+ cells promotes immune activation during vesicular stomatitis virus infection' Journal of Virology, vol. 92, no. 3, e01637-17, pp. 1-18. https://doi.org/10.1128/JVI.01637-17
Wu, G, Nagala, M & Crocker, PR 2017, 'Identification of lectin counter-receptors on cell membranes by proximity labelling' Glycobiology, vol. 27, no. 9, pp. 800-805. https://doi.org/10.1093/glycob/cwx063
Konishi, H, Kobayashi, M, Kunisawa, T, Imai, K, Sayo, A, Malissen, B, Crocker, PR, Sato, K & Kiyama, H 2017, 'Siglec-H is a microglia-specific marker that discriminates microglia from CNS-associated macrophages and CNS-infiltrating monocytes' Glia, vol. 65, no. 12, pp. 1927-1943. https://doi.org/10.1002/glia.23204
Schofield, CL, Marín, MJ, Rejzek, M, Crocker, PR, Field, RA & Russell, DA 2016, 'Detection of mSiglec-E, in solution and expressed on the surface of Chinese hamster ovary cells, using sialic acid functionalised gold nanoparticles' Analyst, vol. 141, no. 20, pp. 5799-5809. https://doi.org/10.1039/c6an01230b
Brown, GD & Crocker, PR 2016, 'Lectin receptors expressed on myeloid cells' Microbiology Spectrum, vol. 4, no. 5, pp. 1-26. https://doi.org/10.1128/microbiolspec.MCHD-0036-2016
Zhang, Y, Roth, TL, Gray, EE, Chen, H, Rodda, LB, Liang, Y, Ventura, P, Villeda, S, Crocker, PR & Cyster, JG 2016, 'Migratory and adhesive cues controlling innate-like lymphocyte surveillance of the pathogen-exposed surface of the lymph node' eLife, vol. 5, e18156, pp. 1-29. https://doi.org/10.7554/eLife.18156
Perdicchio, M, Ilarregui, JM, Verstege, MI, Cornelissen, LAM, Schetters, STT, Engels, S, Ambrosini, M, Kalay, H, Veninga, H, Den Haan, JMM, Van Berkel, LA, Samsom, JN, Crocker, PR, Sparwasser, T, Berod, L, Garcia-Vallejo, JJ, Van Kooyk, Y & Unger, WWJ 2016, 'Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells' Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 12, pp. 3329-3334. https://doi.org/10.1073/pnas.1507706113
Crocker, PR & Mohan, B 2016, Sialylation and immune surveillance of cancer by siglecs. in Glycosignals in Cancer: Mechanisms of Malignant Phenotypes. Springer Japan, pp. 125-138. https://doi.org/10.1007/978-4-431-55939-9_8
Beatson, R, Tajadura-Ortega, V, Achkova, D, Picco, G, Tsourouktsoglou, T-D, Klausing, S, Hillier, M, Maher, J, Noll, T, Crocker, PR, Taylor-Papadimitriou, J & Burchell, JM 2016, 'The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9' Nature Immunology, vol. 17, no. 11, pp. 1273-1281. https://doi.org/10.1038/ni.3552
Griseri, T, Arnold, IC, Pearson, C, Krausgruber, T, Schiering, C, Franchini, F, Schulthess, J, McKenzie, BS, Crocker, PR & Powrie, F 2015, 'Granulocyte macrophage colony-stimulating factor-activated eosinophils promote interleukin-23 driven chronic colitis' Immunity, vol. 43, no. 1, pp. 187-200. https://doi.org/10.1016/j.immuni.2015.07.008
Shao, B, Yago, T, Setiadi, H, Wang, Y, Mehta-D'Souza, P, Fu, J, Crocker, PR, Rodgers, W, Xia, L & McEver, RP 2015, 'O-glycans direct selectin ligands to lipid rafts on leukocytes' Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 28, pp. 8661-8666. https://doi.org/10.1073/pnas.1507712112
Crocker, PR & Kannagi, R 2014, 'Introduction to special issue: 'emerging roles of siglecs in health and disease'' Glycobiology, vol. 24, no. 9, pp. 784-784. https://doi.org/10.1093/glycob/cwu073
Pearce, OMT, Läubli, H, Verhagen, A, Secrest, P, Zhang, J, Varki, NM, Crocker, PR, Bui, JD & Varki, A 2014, 'Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies' Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 16, pp. 5998-6003. https://doi.org/10.1073/pnas.1209067111
Bradford, BM, Crocker, PR & Mabbott, NA 2014, 'Peripheral prion disease pathogenesis is unaltered in the absence of sialoadhesin (Siglec-1/CD169)' Immunology, vol. 143, no. 1, pp. 120-129. https://doi.org/10.1111/imm.12294
Stephenson, HN, Mills, DC, Jones, H, Milioris, E, Copland, A, Dorrell, N, Wren, BW, Crocker, PR, Escors, D & Bajaj-Elliott, M 2014, 'Pseudaminic acid on Campylobacter jejuni flagella modulates dendritic cell IL-10 expression via Siglec-10 receptor: a novel flagellin-host interaction' Journal of Infectious Diseases, vol. 210, no. 9, pp. 1487-1498. https://doi.org/10.1093/infdis/jiu287
Chang, Y-C, Olson, J, Louie, A, Crocker, PR, Varki, A & Nizet, V 2014, 'Role of macrophage sialoadhesin in host defense against the sialylated pathogen group B Streptococcus' Journal of Molecular Medicine, vol. 92, no. 9, pp. 951-959. https://doi.org/10.1007/s00109-014-1157-y
McMillan, SJ, Sharma, RS, Richards, HE, Hegde, V & Crocker, PR 2014, 'Siglec-E promotes β2-integrin-dependent NADPH oxidase activation to suppress neutrophil recruitment to the lung' Journal of Biological Chemistry, vol. 289, no. 29, pp. 20370-20376. https://doi.org/10.1074/jbc.M114.574624
McMillan, SJ, Richards, HE & Crocker, PR 2014, 'Siglec-F-dependent negative regulation of allergen-induced eosinophilia depends critically on the experimental model' Immunology Letters, vol. 160, no. 1, pp. 11-16. https://doi.org/10.1016/j.imlet.2014.03.008
Macauley, MS, Crocker, PR & Paulson, JC 2014, 'Siglec-mediated regulation of immune cell function in disease' Nature Reviews Immunology, vol. 14, no. 10, pp. 653-666. https://doi.org/10.1038/nri3737
McMillan, S.J., Sharma, R.S., McKenzie, E.J., Richards, H.E., Zhang, J., Prescott, A., and Crocker, P.R. (2013). Siglec-E is a negative regulator of acute pulmonary neutrophil inflammation and suppresses CD11b beta2-integrin-dependent signaling. Blood 121, 2084-2094.
Kidder, D., Richards, H.E., Ziltener, H.J., Garden, O.A., and Crocker, P.R. (2013). Sialoadhesin ligand expression identifies a subset of CD4+Foxp3- T cells with a distinct activation and glycosylation profile. J Immunol 190, 2593-2602.
Klaas, M., Oetke, C., Lewis, L.E., Erwig, L.P., Heikema, A.P., Easton, A., Willison, H.J., and Crocker, P.R. (2012). Sialoadhesin promotes rapid proinflammatory and type I IFN responses to a sialylated pathogen, Campylobacter jejuni. J Immunol 189, 2414-2422.
Klaas M, Crocker PR. (2012) Sialoadhesin in recognition of self and non-self. Semin Immunopathol. 34:353-64.
Crocker PR, McMillan SJ, Richards HE. (2012) CD33-related siglecs as potential modulators of inflammatory responses. Ann N Y Acad Sci. 1253:102-11.
Redelinghuys, P., Antonopoulos, A., Liu, Y., Campanero-Rhodes, M. A., McKenzie, E.,Haslam, S. M., Dell, A., Feizi, T. and Crocker, P. R. (2011) Early Murine T-lymphocyte Activation Is Accompanied by a Switch from N-Glycolyl- to N-Acetyl-neuraminic Acid and Generation of Ligands for Siglec-E. J Biol Chem. 286, 34522-34532.
Our research is expected to have impact on human immune and inflammatory diseases in terms of our basic understanding of the underlying pathologies. In the long-term, this may lead to improved therapies.