Sinusoidal immunity: macrophages at the lymphohematopoietic interface

Abstract

Macrophages are widely distributed throughout the body, performing vital homeostatic and defense functions after local and systemic perturbation within tissues. In concert with closely related dendritic cells and other myeloid and lymphoid cells, which mediate the innate and adaptive immune response, macrophages determine the outcome of the inflammatory and repair processes that accompany sterile and infectious injury and microbial invasion. This article will describe and compare the role of specialized macrophage populations at two critical interfaces between the resident host lymphohematopoietic system and circulating blood and lymph, the carriers of cells, humoral components, microorganisms, and their products. Sinusoidal macrophages in the marginal zone of the spleen and subcapsular sinus and medulla of secondary lymph nodes contribute to the innate and adaptive responses of the host in health and disease. Although historically recognized as major constituents of the reticuloendothelial system, it has only recently become apparent that these specialized macrophages in close proximity to B and T lymphocytes play an indispensable role in recognition and responses to exogenous and endogenous ligands, thus shaping the nature and quality of immunity and inflammation. We review current understanding of these macrophages and identify gaps in our knowledge for further investigation.

Figure 1.

Sinusoidal resident tissue macrophages in the mouse. (A) F4/80⁺ Kupffer cells, distinct from F4/80-sinusoidal endothelium and adjacent hepatocytes. Bone marrow stromal macrophages in situ (B), and in vitro (C). These F4/80⁺ macrophages associate with clusters of hematopoietic cells during their differentiation and express CD169 at sites of contact with myeloid cells (D). (From Hume et al. 1983 and Crocker et al. 1990; reprinted, with permission.)

Figure 2.

Schematic representation of mouse spleen and lymph node. Illustrating the lymphohematopoietic interface with specialized macrophages in close proximity to B- and T- lymphocyte populations. (From Gordon 2012 and Martinez-Pomares and Gordon 2012; adapted, with permission.)

Figure 3.

Schematic diagram of plasma membrane glycoproteins used to characterize sinusoidal and related molecules in mouse lympho-hematopoietic tissues. CR-Fc is a soluble chimaeric protein derived from the cysteine-rich domain of the mannose receptor and human Fc.

Figure 4.

Immunocytochemistry of mouse spleen. (A) F4/80⁺ red pulp macrophages. Note the absence of F4/80 expression in marginal zone. (B–F) CD169⁺ marginal metallophilic macrophages. (C–F) Subpopulations of CD169⁺ bind CR-Fc and associate with IgD⁺ B lymphocytes (D, panel on right). E and F illustrate induced migration of CR-Fc⁺ macrophages into white pulp after immune activation. (From Crocker and Gordon 1989 and Taylor et al. 2004; reprinted, with permission, from The Rockefeller University © 1989 and the authors.)

Figure 5.

Spleen and lymph node in wild type and CSF-1-deficient op/op mice. CD169 expression by marginal metallophilic macrophages (A,B), and subcapsular macrophages (C,D) depends on CSF-1. (From Witmer-Pack et al. 1993; reprinted, with permission, from the authors.)

Figure 6.

Functions of marginal zone macrophages. (A,B) Splenic MARCO⁺ marginal zone macrophages clear calciprotein particles from the circulation. (From Herrmann et al. 2012; reprinted, with permission.) (C,D) F4/80⁺ APC (magenta) localize to marginal zone of spleen after induction of tolerance to antigen delivered into the anterior chamber of the eye; CD169⁺ marginal metallophilic macrophages in green. (From Lin et al. 2005; reprinted, with permission, from the authors.)

Figure 7.

Sinusoidal macrophages in lymph node. (A–C) CD169⁺ subcapsular sinus macrophages in proximity to CD11c⁺ DC and B220⁺ B lymphocytes. Scale bar, 50 μm. (D) Adjacent cells in the medullary sinus express MR and Lyve-1. (E) F4/80⁺ macrophages in the medulla. (A–D, From Asano et al. 2011; reprinted, with permission, from the authors; E, from Hume et al. 1983; reprinted, with permission, from the authors.)

Figure 8.

Schematic representation of subcapsular sinus macrophage function: antigen capture, delivery, and activation of B lymphocytes. For details, see text. (From Martinez-Pomares and Gordon 2007; reprinted, with permission, from the authors.)