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Siamon Gordon: a Half-Century Fascination with Macrophages

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Siamon Gordon: a Half-Century Fascination with Macrophages PEOPLE & IDEAS Siamon Gordon: A half-century fascination with macrophages Stephanie Houston Siamon Gordon is a Glaxo Wellcome Professor Emeritus of Cellular Pathology at the University of Oxford and a fellow of the Royal Society. Throughout his career, Siamon has focused on macrophages, and his work led to the identification of the pan- macrophage marker F4/80 and the description of a role for Dectin-1 in the innate recognition of β-glucans. I caught up with Siamon to discuss his career path and his thoughts on macrophages. Downloaded from http://rupress.org/jem/article-pdf/217/7/e20191069/1138520/jem_20191069.pdf by guest on 26 September 2021 Background plasma membrane receptors and respon- My parents immigrated to South Africa siveness to change in their environment, from Lithuania in 1930. Due to the Depres- they support specific organ functions and sion, my father, trained as a rabbi, had to promote homeostasis beyond immunity and move to the small village of Darling, 50 host defense. miles from Cape Town, to serve a scattered Jewish community on the West Coast. I Where and with whom have you studied spoke Afrikaans and went to a local school (undergraduate, graduate, postdoc)? until the age of 15 before moving to an In 1965, I was fortunate to meet my doctoral English language school in Cape Town for supervisor, Zanvil (Zan) Cohn, founder of the final 2 yr of high school. I studied med- cellular immunology at the Rockefeller icine at the University of Cape Town, grad- University, mentor of a generation of mac- uating in 1961, completed my residency at rophage investigators, and editor of the Groote Schuur Hospital, and left for further Journal of Experimental Medicine.Heen- research experience abroad in 1964. After a couraged me to use primary mouse macro- year in the laboratory of Rodney Porter at phages as a fusion partner for Sendai the Wright-Fleming Institute in London and virus–induced hybridization with a malig- a further year with Alexander Bearn at the nant melanoma cell line. This experimental Rockefeller University in New York, I joined approach to studying somatic cell prolifer- the doctoral program at Rockefeller in 1966. ation and differentiation had been pio- Siamon Gordon neered by Henry Harris at Oxford (Harris, When did your interest in 1966). I could not foresee that I would move and environmentalist ReneDubos,were´ macrophages begin? to the Sir William Dunn School of Pathology influential in the field of leukocyte biology I have been devoted to macrophages for over in 1976 for the rest of my career, focusing on and helped to motivate the change in no- 50 yr, as a student, group leader, and men- macrophages for their own sake, on occa- menclature from “reticuloendothelial” to tor. After early experiments at Rockefeller sion reverting to cell fusion as a tool and “mononuclear phagocyte system” (van with macrophages as a fusion partner for phenomenon. A portrait of Elie Metchnik- Furth et al., 1972). somatic cell genetics, I chose to study their off, the grandfather of macrophage im- role in inflammation for its own sake, as munobiology, hung in the office of James Why are macrophages such important phagocytes and secretory cells. At Oxford, (Jim) Hirsch, codirector of the laboratory, cells to study? my group developed mAb to study their and cast a benign presence over the group. Macrophages constitute a dispersed organ distribution and function as the mononu- This was a time of rapid progress in cell of cells distributed throughout different clear phagocyte system, representing a dis- biology at Rockefeller, initiated by Palade, body compartments from embryonic de- persed organ in all tissues of the body, de Duve, Siekevitz, Allfrey, and, later, Blo- velopment to adult life, adapted to respond throughout health and disease. Through bel. Zan and Jim, proteg´ es´ of microbiologist to diverse tissue environments, internal ............................................................................................................................................................................. [email protected]. © 2020 Houston. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). Rockefeller University Press https://doi.org/10.1084/jem.20191069 1of3 J. Exp. Med. 2020 Vol. 217 No. 7 e20191069 tissues with high turnover such as gut and are recruited in response to increased de- mands during inflammation and infection. Adult tissues therefore contain mosaic macrophage populations of embryonic and bone marrow origin. Immunocytochemical analysis of antigen markers established that macrophages can be distinguished from other cell types in situ; particularly striking was the dis- covery that resident macrophages in dif- ferent organs expressed tissue-specific signatures as well as common antigen markers. Recent gene expression analysis by single-cell RNA sequencing has begun to Downloaded from http://rupress.org/jem/article-pdf/217/7/e20191069/1138520/jem_20191069.pdf by guest on 26 September 2021 generate a wealth of information regarding Group reunion in 2013, 5 yr after closing the laboratory. cellular composition and diversity in differ- ent tissues, including macrophage pop- ulations. Although further validation of changes, and exogenous stimuli. As mi- capacity to secrete plasminogen activator, protein expression is needed, this informa- grating and sessile cells, they interact with generating the fibrinolytic enzyme plasmin, tion has already greatly extended knowledge neighboring and remote cells through a va- as well as other potent neutral proteinases, of organ-specific functions; atlases of tissue riety of recognition receptors and secretory collagenase and elastase. These were early and blood cell composition and gene and responses, by direct contact and via soluble indications that macrophages are heteroge- protein expression document extensive cel- signals, to tailor tissue-specificgeneand neous in phenotype, depending on their in- lular heterogeneity, novel cell types, and protein expression. Macrophage trophic, flammatory status. subpopulations of macrophages as well as phagocytic, and digestive functions con- other lineages (https://www.proteinatlas. tribute to organ development, growth, cel- Macrophage heterogeneity is a org/humanproteome/tissue). lular injury, and death, shaping tissue well-established concept. What are Mackaness and colleagues initially de- modeling and repair, as well as host defense your insights? scribed macrophage activation by acquired against infection. By sensing and reacting to Upon setting up my own laboratory at Ox- immunity after Bacille-Calmette-Guerin´ changes in their immediate and systemic ford, it was natural to use hybridoma tech- (BCG) infection; enhanced anti-mycobacterial environment, macrophages contribute to nology to generate new tools to characterize activity depended on prior stimulation of T physiological homeostasis as well as many macrophage heterogeneity in situ. Hybridi- lymphocytes but was antigen nonspecific, disease processes beyond innate and adap- zation of immunized splenic B lymphocytes since priming by BCG also promoted resis- tive immunity. and myeloma cells yielded cell-specific mAb. tance to challenge with Listeria monocytogenes, Mouse peritoneal macrophages were a The pan-macrophage F4/80 mAb (Austyn an unrelated pathogen (Mackaness, 1964). wonder to behold by phase-contrast mi- and Gordon, 1981), directed against the Subsequent studies by Steinman and Cohn croscopy, especially after inflammatory EMR1 antigen, made it possible to identify revealed the role of dendritic cells in the ac- stimulation in vivo and isolation by their mouse macrophages in embryonic and adult tivation of naive CD4 lymphocytes (Moberg, tenacious adhesion to tissue culture plastic tissues in the steady-state and a range of 2011), and others identified interferon gamma in vitro. Their pseudopodia and dynamic disease models. Functional screens were as the macrophage-activating cytokine. Many membrane ruffles, combined with a busy subsequently used to develop a panel of studies of resident and monocyte-recruited cytoplasm of endocytic and secretory vesi- further mAb directed against macrophage tissue macrophages in inflammation and in- cles, captured my imagination. Macrophage- surface receptors involved in adhesion, mi- fection revealed striking differences in mac- specific markers such as the phagocytic Fc gration and phagocytosis (Taylor et al., rophage phenotype associated with innate receptors were extinguished in hetero- 2005). and adaptive, humoral, and cellular immu- karyons by fusion with melanoma cells, but Fast forward to the past decade, during nity; prominent changes were observed were, however, retained in immortalized which a paradigm shift has been brought in MHC and costimulatory antigen expres- hybrids by fusing primary macrophages about by lineage-tracing methods, that sion, generation of reactive oxygen and ni- with a macrophage tumor cell line. The macrophages in tissues originate from yolk trogen metabolites, and secretion of pro- and discovery that macrophage primary cells sac and fetal liver progenitors which seed anti-inflammatory cytokines, enzymes, and and hybrids constitutively released lyso- developing
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