Page 1100 - Williams Hematology ( PDFDrive )

1075

CHAPTER 68 used to knock down macrophage genes or messenger RNA, and to mark
cells with fluorescent labels such as green fluorescent protein. Of par-
PRODUCTION, ticular value in tracing their origins and distribution has been the use
2
of fractalkine receptor-transgenics, and myeloid-specific lysozyme-Cre
3
DISTRIBUTION, AND for targeted ablation. Random chemical mutagenesis has been spectac-
ularly successful in validating known, and discovering novel, gene tar-
4,5
gets that affect macrophage functions. A wider range of experimental
ACTIVATION OF MONOCYTES models (Drosophila, zebra fish) have facilitated interspecies compari-
6,7
sons of macrophage migration and phagocytosis in vivo. The analysis
8
AND MACROPHAGES of microRNA expression and functions is still in its infancy and is likely
to generate important insights into monocyte/macrophage gene expres-
sion in health and disease. Combined with improved imaging meth-
ods (fluorescent, nuclear magnetic resonance imaging-based, 2-photon
Steven D. Douglas and Anne G. Douglas microscopy), new insights have been obtained regarding the dynamic
9
behavior of macrophages and dendritic cells (DCs) in vivo. There has
been progress in provoking embryonic and induced pluripotent stem
cell differentiation into macrophages and DCs in vitro, opening the
SUMMARY possibility of introducing mutations into human genes, to complement
the naturally occurring material derived from human inborn errors and
Monocytes and macrophages play an important role in human biology, both resultant genetic diseases. 10
as a component of the hematopoietic system and within the stroma and tissue Although individual-labeled cells can be followed in accessible
microenvironment where they contribute trophic and clearance functions. They tissues or ex vivo, the resolution, isolation, and characterization of
important embedded macrophage populations are limiting. Methods
constitute a widely dispersed cellular system throughout the body, interacting of isolation from solid organs, for example, brain and even liver and
with host cells and foreign invaders through their versatile biosynthetic and gut, are prone to artifact, and macrophages are profoundly affected by
secretory responses, to maintain physiologic homeostasis. They are specialized removal from their natural tissue environment. Many of the genetic
migratory or sessile phagocytes, present within the circulation and extravascu- manipulations introduced by transgenesis are leaky and not uniform,
lar tissue compartment, contributing to diverse pathologic processes directly not surprising in the light of macrophage heterogeneity. Although the
and through their production of bioactive products. Because of their exten- fate of recently recruited cells from blood into tissues can be tracked
sive heterogeneity and plasticity, the centrality of monocytes and their prog- more easily, the slowly turning over resident populations are less easily
eny has not always been recognized by hematologists. The origin, life span, accessed, resulting in bias. Finally, there are intrinsic difficulties with
and functions of the monocyte are the focus of this chapter, including their human experimentation in vivo. Induced skin blisters, for example,
11
relevance to health and disease in humans, based on current understanding make it possible to collect fluid and cells from sites of inflammation.
of their properties. The relationship of monocytes and macrophages to den- However, the low frequency of monocytes compared with neutrophils
limits the use of ex vivo indium-labeled cells for transfer studies in vivo.
dritic cells, and monocyte-derived cells with a specialized immunologic role in
T-lymphocyte activation, are described. Together, macrophages and dendritic
cells are major antigen-presenting cells, contributing to host defense, innate PRODUCTION
and acquired immunity, and inflammation, as well as noninfectious disease
processes, both within and outside the lymphohematopoietic organs. DEVELOPMENT OF MONOCYTES
AND MACROPHAGES
Macrophages and related amoeboid phagocytic cells, ancient in the
METHODS OF MONOCYTE AND evolution of multicellular organisms, are the main leukocytes respon-
sible for innate immunity and tissue remodeling, as documented by
MACROPHAGE STUDY Metchnikoff in his pioneering studies on invertebrates, and confirmed
12
by contemporary studies on Drosophila melanogaster. In mammals,
7
There has been a resurgence of interest in the in situ analysis of much of our knowledge of macrophage ontogeny derives from studies
macrophages. Genetic/ribonucleic acid interference manipulation, in the mouse. After origins from an aortic mesonephric site, the best
1
more recently with macrophage-specific/restricted promoters, has been understood phases of macrophage development occur during midfetal
development, in the yolk sac, followed by fetal liver, spleen, and marrow,
before and after birth. The association of macrophages with definitive
13
Acronyms and Abbreviations: CR, complement receptor; DC, dendritic cell; DC- erythropoiesis is a striking feature of fetal liver hematopoiesis from
SIGN, dendritic cell–specific intercellular adhesion molecule-3–grabbing noninteg- approximately day 12 of mouse development; macrophages then, for the
rin; EMR, epidermal growth factor module-containing mucin-like hormone receptor; first time, become intimately associated with nucleated erythroblasts,
FACS, fluorescence-activated cell sorting; FcR, Fc receptor; GM-CSF, granulocyte- reaching a peak of hematopoietic cluster formation at day 14. The role
macrophage colony-stimulating factor; IFN-γ, interferon-γ; IL, interleukin; LPS, of stromal macrophages in hematopoiesis within the adult is illustrated
lipopolysaccharide; M-CSF, macrophage colony-stimulating factor; MARCO, macro- and discussed further in this chapter.
phage receptor with a collagenous structure; MR, mannose receptor; PRR, pattern The association of macrophages with erythroblasts is mediated by
recognition receptor; Sn, sialoadhesin; SR-A, scavenger receptor A; TGF, transforming surface adhesion molecules, including a poorly characterized diva-
14
growth factor; TLR, toll-like receptor; TNF-α, tumor necrosis factor-α.
lent cation-dependent receptor and the sialic acid-binding molecule
15
sialoadhesin (Siglec1). The potential trophic functions of stromal

Kaushansky_chapter 68_p1075-1088.indd 1075 9/17/15 3:41 PM