Metchnikoff's Legacy: Tissue Phagocytes and Functions

Abstract

Macrophages represent a dispersed population of myeloid phagocytes that are widely distributed within the body, performing vital homeostatic as well as trophic and immune effector functions throughout life. They adopt a strikingly heterogeneous phenotype in liver, lung, gut, brain, bone, skin, as resident cells in the absence of inflammation, and as recruited cells in response to sterile stimuli, as well as infectious micro-organisms. They are specialised phagocytes, yet also active secretory cells, interacting reciprocally with every other cell type. Phagocytosis was recognised and studied for the first time following the observations of the Russian scientist Elie Metchnikoff (1845-1916) during his stay in the Sicilian city of Messina (1882) that opened the field of cellular immunity, at that time untrendy and unexplored. During this year we mark the centenary of the death of this great scientist, which closely followed that of Paul Ehrlich (1854-1915), the leader of humoral immunity theory, with whom he shared the 1908 Nobel Prize. The EFIS-EJI Ruggero Ceppellini Advanced School of Immunology takes place every year 1. This time the course was celebrated in the Stazione Zoologica “Anton Dohrn” in Naples, Italy on the 12–14 October 2016. Siamon Gordon (Oxford), Stefan H.E. Kaufmann (Berlin) and Fernando Martinez-Estrada (Surrey) were the directors. The programme of this course covered macrophage topics of current research and clinical interest, attesting to their remarkable versatility in health and disease. An articulated round table opened the course with the participation of Siamon Gordon (Oxford), Giuseppe Teti (Messina), Helmut Hahn (Berlin), Vitaly Zverev (Moscow) and Massimiliano Maja (Stazione Zoologica, Naples). This discussion helped the participants put into the proper historical perspective all the developmental aspects of the huge wealth of studies and advancements in this central field of Immunology. The first lecture, delivered by Muzlifah Haniffa (Newcastle), made the audience aware of the great complexity of the macrophage and macrophage-derived cells resident in many tissues of the body, and that comparative biology analysis between mouse and human is a useful tool to harmonize findings across species 2. The subsequent presentation by the director of the course Siamon Gordon (Oxford), provided a comprehensive overview of the macrophage distribution and function, where heterogeneity of the cell types, their location and their longevity have a profound effect on recognition and response 3. Ela Kolaczkowska (Krakow) showed, with truly exciting motion pictures, how the newly developed intravital microscopy (aka in vivo microscopy), by which vasculature and tissues of live animals can be observed in real time, was critical for the discovery of some steps of the leukocyte recruitment cascade, leading to diapedesis and transmigration into the tissues 4. Apoptosis and its management by phagocytes was the issue of Kodi Ravichandran's (Charlottesville, VA) presentation, who discussed the “find me” signals sent by the apoptotic cells and the “eat me” signals in form of nucleotides sensed by the phagocytes’ receptors to distinguish between normal cells and dying ones 4. Anna Katharina Simon (Oxford) underlined in her lecture the importance of autophagy, an intracellular highly conserved pathway responsible for the delivery of cytoplasmic material to the lysosome, in the maintenance of a highly efficient phagocytic capacity in infection and its involvement in neurodegenerative diseases as well as in cancer, cardiomyopathy, type II diabetes and ageing 5. In his speech Giuseppe Teti (Messina) covered the complex field of recognition of “non self” by specialised cells such as macrophages that present, both on their cellular surface as well as inside the cytoplasm, receptors for chemical structures associated with microorganisms including their DNA or RNA sequences 5. The complexity of the Interleukin-1 Receptor (IL-1R) family, that includes signaling receptor complexes, decoy receptors, and negative regulators, was the subject of the lesson of Cecilia Garlanda (Milan), that particularly focused on the IL-1R8 and its role in different pathological conditions ranging from infectious and sterile inflammation to autoimmunity and cancer. The biology and functions of the pentraxin system was also covered 6. The co-director of the course and Scientific Director of the School Stefan H.E.Kaufmann (Berlin) centred his speech on the evergreen problem of tuberculosis (TB) vaccination, especially defining gene expression signatures that could distinguish between latent TB infection and active disease. Information from such signatures has pointed to a distinct role of excessive inflammation in TB with neutrophils playing a central role. Modulating the action of those cells might open the way to novel intervention strategies against TB 7. In the lecture that followed, F.Y.(Eddy) Liew (Glasgow) directed the audience's attention on the latest discovered member of the IL-1 family, IL-33, that is the ligand of ST2 (suppression of tumorigenicity 2) which is expressed mainly on Th2 cells, epithelial cells, neuronal cells and mast cells. IL-33 shows promising effects in the attenuation of sepsis, reduction of experimental malaria and amelioration of the symptoms of Alzheimer disease. In this latter case IL-33 seems to stimulate the M2 phagocytic function in the microglia that reduces the beta-amyloid deposits around the nerves 8. The next instructor Quentin Sattentau (Oxford) showed in his lecture the strategy used by HIV-1 to induce apoptotic signals from infected CD4+ in order to be taken up by macrophages, favouring their anti-inflammatory phenotypes and maintaining the infection in the body 9. The relationship between the presence of macrophages, especially those bearing the CD169+ phenotype, and the resistance to the infection of Ebola virus and the more recently studied Nipah virus was presented in the lecture of Branka Horvat (Lyon), who underlined the importance of macrophage studies also in the emerging viral infections 10. Labile iron, beside being essential to support life functions, is also capable of catalyzing the production of reactive oxygen species and becoming pro-oxidant and cytotoxic. The delicate balance between these two aspects of iron metabolism is governed by the macrophages, as was shown in the presentation of Miguel P. Soares (Oeiras), disclosing another important function of those pluripotent cells 11. The gut is a big arena where microbes and immune cells come into contact and where it is decided whether this encounter is immunogenic or tolerogenic. Maria Rescigno (Milan) in her presentation provided evidence that some bacteria are tolerogenic and other pathogenic, according to their capacity of being fixed by the mucus and internalized by the cells of the intestinal mucosa. Lack of mucus is an obstacle to this internalization and its consequent encounter with gut dendritic cells (GDCs). No IgA that controls mucus production is therefore induced, and a non tolerogenic reaction follows with an inflammatory outcome within the organ 12. Exposure to a variety of danger signals, namely molecules released from damaged tissues or invading microorganisms, induce dramatic changes in macrophage activity and gene expression programs. Gioacchino Natoli (Milan) with his lecture suggested that lineage-determined transcription factors that specify macrophage development also condition signal-regulated transcription factors, creating a genomic landing platform specific for individual cell types, diversifying the gene expression programs determined by identical stimuli 13. Diego Gomez-Nicola (Southampton) reviewed the studies on the dynamics and functions of microglia, the brain's resident myeloid cells, and its role in surveillance, proliferation, pruning, phagocytosis and inflammation in health and pathological conditions such as Alzheimer and Amyotrophic Lateral Sclerosis 14. The struggle over the definition of different macrophage subsets was addressed by the lecture of Fernando Martinez-Estrada (Surrey) who suggested that the proposed M1/M2 dichotomy for macrophage activation does not necessarily correspond to two distinctive cell populations, but that the different function of the cells is determined by a combination of factors present in the tissues, attributing both potentials to the same cell 15. The course concluded with the lecture of Vincenzo Bronte (Verona) on myeloid-derived suppressor cells (MDSCs). Two main subsets of these cells have been identified with different phenotypic and biological properties: monocytic MDSCs and polymorphonuclear MDSCs. The modulation of the function of those cells by chemo-immunotherapy might be of help in improving the efficacy of current therapy of cancer 16. Qualified students from 25 countries participated with enthusiasm and vivacious cultural curiosity in this Ceppellini course, that was by the vast majority of them considered fruitful for their career as young immunologists (Fig. 1). Discussions between the audience and the teaching staff took place formally after each lecture and informally during lunches and coffee breaks, with great satisfaction on both parties. The prestigious venue of the three day event, the Zoological Station “Anton Dohrn” of Naples, represented the most appropriate location to celebrate the centennial of one of its most prominent scientist visitors. This successful course marks 25 years of high-quality immunological courses offered by the Ruggero Ceppellini School.