Rate of replenishment and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages

International audienceMacrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the aetiology of pathologies including peritonitis, endometriosis and metastatic cancer thus understanding the factors that govern their behaviour is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover and function. We demonstrat

The development and maintenance of the mononuclear phagocyte system of the chick is controlled by signals from the macrophage colony-stimulating factor (CSF1) receptor

BACKGROUND: Macrophages have many functions in development and homeostasis as well as innate immunity. Recent studies in mammals suggest that cells arising in the yolk sac give rise to self-renewing macrophage populations that persist in adult tissues. Macrophage proliferation and differentiation is controlled by macrophage colony-stimulating factor (CSF1) and interleukin 34 (IL34), both agonists of the CSF1 receptor (CSF1R). In the current manuscript we describe the origin, function and regulation of macrophages, and the role of CSF1R signaling during embryonic development, using the chick as a model. RESULTS: Based upon RNA-sequencing comparison to bone marrow-derived macrophages grown in CSF1, we show that embryonic macrophages contribute around 2% of the total embryo RNA in day 7 chick embryos, and have similar gene expression profiles to bone marrow-derived macrophages. To explore the origins of embryonic and adult macrophages, we injected Hamburger-Hamilton stage 16 to 17 chick embryos with either yolk sac-derived blood cells, or bone marrow cells from EGFP(+) donors. In both cases, the transferred cells gave rise to large numbers of EGFP(+) tissue macrophages in the embryo. In the case of the yolk sac, these cells were not retained in hatched birds. Conversely, bone marrow EGFP(+) cells gave rise to tissue macrophages in all organs of adult birds, and regenerated CSF1-responsive marrow macrophage progenitors. Surprisingly, they did not contribute to any other hematopoietic lineage. To explore the role of CSF1 further, we injected embryonic or hatchling CSF1R-reporter transgenic birds with a novel chicken CSF1-Fc conjugate. In both cases, the treatment produced a large increase in macrophage numbers in all tissues examined. There were no apparent adverse effects of chicken CSF1-Fc on embryonic or post-hatch development, but there was an unexpected increase in bone density in the treated hatchlings. CONCLUSIONS: The data indicate that the yolk sac is not the major source of macrophages in adult birds, and that there is a macrophage-restricted, self-renewing progenitor cell in bone marrow. CSF1R is demonstrated to be limiting for macrophage development during development in ovo and post-hatch. The chicken provides a novel and tractable model to study the development of the mononuclear phagocyte system and CSF1R signaling. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-015-0121-9) contains supplementary material, which is available to authorized users

Mechanisms of Notch signaling specificity in lymphocytes and their leukemic counterparts

Signaling pathways have evolved to ensure that external signals are sensed by a cell and translated into changes in gene expression that ultimately determine the differentiation and function of a cell. Mutations in components of signaling pathways uncouple these from the external signals they normally respond to, and thereby constitutively (in)activate these pathways, which can lead to disease, most notably cancer. In this thesis, we studied the role of one such pathway, Notch signaling, in the differentiation and function of lymphocytes and their leukemic counterparts. We identified a new role for Notch signaling in promoting cellular longevity of CD4+ T helper cells (chapter 5), and demonstrated that Notch uses direct and indirect mechanisms to promote differentiation of various T helper cell lineages (chapter 6). We also described a previously unappreciated role for Notch in driving the differentiation of human group 2 innate lymphoid cells (ILC2) (chapter 2) and present indications for the existence of ILC2 like leukemia, which also display mutational activation of the Notch pathway (chapter 3). Finally, we showed that - unlike in mice - human T cell development and sustained growth of T cell acute lymphoblastic leukemia cells do not depend on the ability of NOTCH1 to homodimerize (chapter 4). These findings further elucidate the diverse functions of Notch signaling in lymphocytes and its oncogenic potential in these cells, and therefore have important biomedical implications

Tissue macrophage identity and self-renewal

Macrophages are cellular components of the innate immune system that reside in virtually all tissues and contribute to immunity, repair, and homeostasis. The traditional view that all tissue-resident macrophages derive from the bone marrow through circulating monocyte intermediates has dramatically shifted recently with the observation that macrophages from embryonic progenitors can persist into adulthood and self-maintain by local proliferation. In several tissues, however, monocytes also contribute to the resident macrophage population, on which the local environment can impose tissue-specific macrophage functions. These observations have raised important questions: What determines resident macrophage identity and function, ontogeny or environment? How is macrophage proliferation regulated? In this review, we summarize the current knowledge about the identity, proliferation, and turnover of tissue-resident macrophages and how they differ from freshly recruited short-lived monocyte-derived cells. We examine whether macrophage proliferation can be qualified as self-renewal of mature differentiated cells and whether the concepts and molecular pathways are comparable to self-renewal mechanisms in stem cells. Finally, we discuss how improved understanding of macrophage identity and self-renewal could be exploited for therapeutic intervention of macrophage-mediated pathologies by selectively targeting freshly recruited or resident macrophages

Correction: Epidermal ?? T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult(Journal of Experimental Medicine(2018) 215:12: DOI: 10.1084/jem.20181206)

10.1084/jem.2018120611142018cJournal of Experimental Medicine21512321

Differentiation and tissue-adaptation of type-2 innate lymphoid cells during helminth infection

2nd Joint Meeting of the German-Society-for-Immunology (DGfl) and the Italian-Society-of-Immunology-Clinical-Immunology-and-Allergology (SIICA), Munich, GERMANY, SEP 10-13, 201