Macrophages and cellular immunity in Drosophila melanogaster

Abstract

The invertebrate Drosophila melanogaster has been a powerful model for understanding blood cell development and immunity. Drosophila is a holometabolous insect, which transitions through a series of life stages from embryo, larva and pupa to adulthood. In spite of this, remarkable parallels exist between Drosophila and vertebrate macrophages, both in terms of development and function. More than 90% of Drosophila blood cells (hemocytes) are macrophages (plasmatocytes), making this highly tractable genetic system attractive for studying a variety of questions in macrophage biology. In vertebrates, recent findings revealed that macrophages have two independent origins: self-renewing macrophages, which reside and proliferate in local microenvironments in a variety of tissues, and macrophages of the monocyte lineage, which derive from hematopoietic stem or progenitor cells. Like vertebrates, Drosophila possesses two macrophage lineages with a conserved dual ontogeny. These parallels allow us to take advantage of the Drosophila model when investigating macrophage lineage specification, maintenance and amplification, and the induction of macrophages and their progenitors by local microenvironments and systemic cues. Beyond macrophage development, Drosophila further serves as a paradigm for understanding the mechanisms underlying macrophage function and cellular immunity in infection, tissue homeostasis and cancer, throughout development and adult life.

Keywords: Antimicrobial peptide; Crystal cell; Development; Drosophila melanogaster; Hematopoiesis; Hematopoietic pockets; Hemocyte; Immunity; Innate immunity; Lamellocyte; Lymph gland; Macrophage; Microenvironment; Monocyte; Plasmatocyte; Self-renewing tissue macrophage; Signaling pathway; Systemic signal.

Figure 1. Ontogeny of macrophages in Drosophila and mouse development

(A) Two waves of hematopoiesis during Drosophila development. The embryonic/larval lineage (in red) originates from the head mesoderm (HM) of the embryo, differentiates in the embryo, and subsequently expands in the larva as self-renewing tissue macrophages (plasmatocytes). The progenitor-based Lymph Gland lineage (in blue) originates in the embryo and differentiates in the late larva. Macrophages of both lineages persist through pupal development into the adult. (B) Three waves of hematopoiesis during mouse development. The primitive wave (in green) emerges in the yolk sac and gives rise to the earliest macrophages; this lineage does not persist after birth. The wave of erythro-myeloid progenitors (EMPs, in red) also emerges in the yolk sac. These cells mature in the fetal liver, and colonize local microenvironments in various organs as tissue-resident macrophages that self-renew and persist. The definitive hematopoietic wave emerges from hemogenic endothelium (major arteries) that give rise to hematopoietic stem cells (HSCs in blue), which colonize the fetal liver and later the bone marrow, giving rise to the monocyte lineage of macrophages.

Figure 2. Blood cell lineages in Drosophila

(A) The embryonic lineage of hemocytes (blood cells) with parallels to self-renewing tissue macrophages in vertebrates. Prohemocyte progenitors (blue) originate in the embryo and differentiate into plasmatocytes (macrophages, red) and a small number of crystal cells (orange); plasmatocytes are quiescent (q) until the end of embryogenesis. In the larva, plasmatocytes colonize local microenvironments, in particular the Hematopoietic Pockets, and expand by self-renewal. Plasmatocytes also give rise to a small number of crystal cells, and, upon immune challenge, lamellocytes (purple). (B) Lymph Gland hematopoiesis with parallels to progenitor-based hematopoiesis in vertebrates. Lymph Gland prohemocytes (blue) are specified from the cardiogenic mesoderm of the embryo. They proliferate at a low rate until the 2nd larval instar, then start differentiating, forming (1) intermediate progenitors and plasmatocytes (red), which expand further by proliferation; (2) crystal cells (orange); (3) lamellocytes (purple). The primary lobe of the differentiating Lymph Gland is organized into a medullary zone (MZ) of quiescent (q) progenitors, and a cortical zone (CZ) of differentiating hemocytes; differentiation of progenitors is completed by 12h after puparium formation. Both lineages of hemocytes are mobilized in the pupa and persist into the adult, where new blood cell production subsides and hemocyte numbers decline. Plasmatocytes and small numbers of crystal cells, but no lamellocytes, are present in the adult.

Figure 3. Innate immune responses in Drosophila

Throughout its life cycle, Drosophila can mount cellular and humoral innate immune responses. Cellular immune responses involve phagoctytosis by plasmatocytes, melanization by crystal cells and lamellocytes, and encapsulation by lamellocytes. Humoral responses involve the induction of antimicrobial peptide (AMP) expression in a number of tissues. In the larva, immune responses include the mobilization of resident plasmatocytes and their differentiation into lamellocytes, and the precocious differentiation and mobilization of Lymph Gland hemocytes. In the adult, hemocytes reside in proximity to tissues of innate immunity and barrier epithelia, such as fat body (brown), respiratory epithelia (purple), gastrointestinal system (teal) and circulatory system (gray).