Regulation of leucocyte homeostasis in the circulation

Abstract

The functions of blood cells extend well beyond the immune functions of leucocytes or the respiratory and hemostatic functions of erythrocytes and platelets. Seen as a whole, the bloodstream is in charge of nurturing and protecting all organs by carrying a mixture of cell populations in transit from one organ to another. To optimize these functions, evolution has provided blood and the vascular system that carries it with various mechanisms that ensure the appropriate influx and egress of cells into and from the circulation where and when needed. How this homeostatic control of blood is achieved has been the object of study for over a century, and although the major mechanisms that govern it are now fairly well understood, several new concepts and mediators have recently emerged that emphasize the dynamism of this liquid tissue. Here we review old and new concepts that relate to the maintenance and regulation of leucocyte homeostasis in blood and briefly discuss the mechanisms for platelets and red blood cells.

Keywords: Cholesterol metabolism; Leucocyte homeostasis; Leucocyte mobilization; Leucocyte recruitment.

Figure 1

Key pathways in the mobilization and recruitment of leucocytes. The key recruitment and mobilization pathways involved in the trafficking of leucocyte populations are exemplified for the bone marrow and lymph node. In the bone marrow (left), leucocytes are recruited from sinusoids via interactions with P- and E-selectin expressed on the endothelium and leucocyte glycoproteins such as PGSL-1. By rolling on the endothelium, leucocytes become activated via CXCR4-CXCL12 interactions and up-regulate the integrin VLA-4, which binds to vascular expressed VCAM-1, to migrate into the parenchyma. Within the bone marrow parenchyma, cells adhere via VLA-4 and CXCR4 with stromal cells expressing VCAM-1 and CXCL12, respectively. The function of CXCR2 can counteract the attractive forces of CXCR4 to induce mobilization in neutrophils. For monocytes, CCR2 detects CCL2 on sinusoidal endothelial cells for mobilization. An egress signal for the mobilization of HSPCs is S1P, which acts via the receptor S1PR1. Within lymph nodes (right) lymphocytes are recruited from blood due to interactions with molecules expressed on HEV. Key factors in this process are the chemokine receptor CCR7, which recognizes the chemokines CCL19 and CCL21. In addition, L-selectin as well as the integrin LFA-1 binds to peripheral node addressins (PNAd) and immunoglobulin superfamily members expressed on HEVs. For their egress, lymphocytes up-regulate S1PR1 and down-modulate the retention factor CCR7. S1PR1 detects higher concentration of S1P in efferent lymph and induces the immigration of cells into lymph and subsequently back into blood.

Figure 2

Cholesterol metabolism and control of leucocyte homeostasis. Modified forms of cholesterol within haematopoietic cells (macrophages or haematopoietic progenitors; HSPC) function as agonists for LXR. Activation of these transcription factors then causes increased transcription of ABC transporters required for cholesterol efflux from the cells and trans-repression of inflammatory cytokines. When LXR or ABC transporters are absent, accumulation of cholesterol in the cells leads to elevated cytokine production (e.g. IL-23) or enhanced signalling through membrane-associated receptors (e.g. IL-3/GM-CSF-R or c-MPL) that promotes leucocyte mobilization, HSPC expansion or thrombocytosis, respectively. Regulation of these processes can occur in extramedullary sites (macrophages in tissues) or in the bone marrow (HSPC or megakaryocytic precursors).