Chronic Brucella Infection Induces Selective and Persistent Interferon Gamma-Dependent Alterations of Marginal Zone Macrophages in the Spleen

Abstract

The spleen is known as an important filter for blood-borne pathogens that are trapped by specialized macrophages in the marginal zone (MZ): the CD209 ϩ MZ macrophages (MZMs) and the CD169 ϩ marginal metallophilic macrophages (MMMs). Acute systemic infection strongly impacts MZ populations and the location of T and B lymphocytes. This phenomenon has been linked to reduced chemokine secretion by stromal cells. Brucella spp. are the causative agent of brucellosis, a widespread zoonotic disease. Here, we used Brucella melitensis infection as a model to investigate the impact of chronic stealth infection on splenic MZ macrophage populations. During the late phase of Brucella infection, we observed a loss of both MZMs and MMMs, with a durable disappearance of MZMs, leading to a reduction of the ability of the spleen to take up soluble antigens, beads, and unrelated bacteria. This effect appears to be selective as every other lymphoid and myeloid population analyzed increased during infection, which was also observed following Brucella abortus and Brucella suis infection. Comparison of wild-type and deficient mice suggested that MZ macrophage population loss is dependent on interferon gamma (IFN-␥) receptor but independent of T cells or tumor necrosis factor alpha receptor 1 (TNF-␣R1) signaling pathways and is not correlated to an alteration of CCL19, CCL21, and CXCL13 chemokine mRNA expression. Our results suggest that MZ macrophage populations are particularly sensitive to persistent low-level IFN-␥-mediated inflammation and that Brucella infection could reduce the ability of the spleen to perform certain MZM-and MMM-dependent tasks, such as antigen delivery to lymphocytes and control of systemic infection.KEYWORDS Brucella melitensis, marginal zone macrophages, low-grade Th1 inflammation, brucellosis, infection, spleen T he spleen is both the largest secondary lymphoid organ and the main filter of blood (for a general review, see reference 1). The white pulp, which contains T and B cell populations, is surrounded by the red pulp, a network of reticular fibers and fibroblasts rich in macrophages, where blood is filtered and old erythrocytes are removed. The marginal zone (MZ) located between the white pulp and the red pulp constitutes a specialized filtering area for blood content. The MZ contains specialized macrophage populations, various dendritic cell (DC) subsets, and MZ B cells. The marginal metallophilic macrophages (MMMs) form an inner ring between the MZ and white pulp, whereas MZ macrophages (MZMs) are situated at the outer boundary of the MZ,

Behavioral and Neurochemical Shifts at the Hippocampus and Frontal Cortex Are Associated to Peripheral Inflammation in Balb/c Mice Infected with Brucella abortus 2308

“…In the case of IFN-γ, the drop in its serum levels by day 21-PI is reminiscent of the kinetics observed for this cytokine in chronic Brucella -infected patients [ 31 ]. The decrease in IFN-γ serum levels observed in mice and humans infected by Brucella may in part be explained by the reduction in the macrophage number in the splenic marginal zone [ 32 ].…”

The Role of Neutrophils in Brucellosis

“…Five days after infection, at the beginning of the acute brucellosis phase (43), there are still negligible numbers of infected PMNs in the target organs but significant recruitment of infected mononuclear phagocytes (42). After 2 weeks of bacterial replication in cells of the reticuloendothelial system, granulomas composed of lymphocytes and infected Ms and DCs become evident, while PMNs are at low numbers and are not infected (42,162).…”

“…4A), peritoneum (Fig. 5B), lungs (35), regional lymph nodes (35), spleen (35,42,162), or gastric mucosa (166). Intratracheal inoculation with a high number of Brucella organisms (10 8 CFU) induces microgranulomas and necrosis in the lungs and granulomas in the liver in the presence of PMNs.…”

Interferon Alpha Favors Macrophage Infection by Visceral Leishmania Species Through Upregulation of Sialoadhesin Expression

“…In the spleen, Sn + macrophages are a subpopulation of tissue-resident macrophages positioned in the splenic marginal zone that are among the first cell types to encounter invading pathogens (47). These splenic Sn + are often referred to as the marginal-zone metallophilic macrophages (46,48,49). In the bone marrow, Sn + macrophages are found in the stroma (19,50,51) and have a scavenging function (19,20).…”