Neutrophils are potent immune effectors against bacterial infections. Macrophages are important in infections as effectors and regulators, but their exact roles, phenotypic characterization and their relation to neutrophils is incompletely understood. Here we report in a model of bacterial urinary tract infection, one of the most prevalent bacterial infections that tissue-resident Ly6C− macrophages recruited circulating neutrophils and inflammatory Ly6C+ macrophages through chemokines. Neutrophils were primarily recruited through ligands of the chemokine receptor CXCR2, in particular by CXCL1 and less by macrophage migration inhibitory factor (MIF), but not through CXCL5 and CXCL2. Neutrophils, but not Ly6C+ macrophages, cleared the bacteria by phagocytosis. Ly6C+ macrophages instead performed a regulatory function: in response to the infection, they produced the cytokine tumor necrosis factor (TNF), which in turn caused the resident macrophages to secrete CXCL2. This chemokine induced the secretion of matrix metalloproteinase-9 (MMP-9) in neutrophils and allowed these cells to degrade the uroepithelial basement membrane, in order to enter the uroepithelium, the mucosal interface from where the bacteria invade the bladder. Thus, the phagocyte response against bacteria is a highly coordinated event, in which Ly6C− macrophages act as sentinels and Ly6C+ macrophages as innate helper cells. In analogy with T helper cells (Th), we propose to name these helper macrophages (Ph) as they provide a second signal on whether to unleash the principal effector phagocytes, the neutrophils. This cellular triage may prevent ‘false-positive’ immune responses. The role of TNF as innate ‘licensing’ factor contributes to its central role in antibacterial immunity.

Abstract-Chronic inflammation in white adipose tissue (WAT) is positively associated with obesity, insulin resistance (IR) and the development of type 2 diabetes. The proinflammatory cytokine MIF (macrophage migration inhibitory factor) is an essential, upstream component of the inflammatory cascade. This study examines whether MIF is required for the development of obesity, IR, glucose intolerance, and atherosclerosis in the LDL receptor-deficient (Ldlr littermates are protected. MIF deficiency does not affect obesity and lipid risk factors but specifically reduces inflammation in WAT and liver, as reflected by lower plasma serum amyloid A and fibrinogen levels at baseline and under inflammatory conditions. Conversely, MIF stimulates the in vivo expression of human C-reactive protein, an inflammation marker and risk factor of IR and cardiovascular disease. In WAT, MIF deficiency reduces nuclear c-Jun levels and improves insulin sensitivity; MIF deficiency also reduces macrophage accumulation in WAT and blunts the expression of two proteins that regulate macrophage infiltration (intercellular adhesion molecule-1, CD44). Mechanistic parallels to WAT were observed in aorta, where the absence of MIF reduces monocyte adhesion, macrophage lesion content, and atherosclerotic lesion size. These data highlight the physiological importance of chronic inflammation in development of IR and atherosclerosis and suggest that MIF is a potential therapeutic target for reducing the inflammatory component of metabolic and cardiovascular disorders. Key Words: inflammation Ⅲ cytokines Ⅲ atherosclerosis Ⅲ insulin resistance Ⅲ C-reactive protein T he intertwined medical problems of obesity, glucose intolerance, type 2 diabetes (T2D), dyslipidemia, and atherosclerosis form the most serious threats to public health worldwide. Insulin resistance (IR) is an integral feature of the medical sequelae that are collectively referred to as the metabolic syndrome. 1 Decreased insulin sensitivity is the underlying defect in Ͼ90% of patients with T2D, and it is also considered to be a major pathological mechanism for the associated development of cardiovascular disease. 2 Recent human and animal studies have established both correlative and causative links between IR and chronic inflammation, in particular within adipose tissue. 3,4 For example, C-reactive protein (CRP), which is a serum marker of systemic inflammation, is independently related to insulin insensitivity and highly predictive for progression to overt T2D. 5 Mechanistic studies that have evaluated the impact of blocking specific inflammatory control points, such as c-Jun N-terminal kinase (JNK)1, 6 support the concept that the persistent activation of proinflammatory transcription factors (eg, c-Jun) in critical metabolic sites (adipose and liver tissue) may underlie the development of IR. When chronically inflamed, these tissues release proinflammatory molecules, including cytokines, acute-phase reactants, and procoagulant factors (eg, interleukin [IL]-6, serum amyloid A [SAA]...

Predictors of severe malarial anemia (altered immune responses, poor nutrition, intestinal parasites, and impaired erythropoiesis) differed from those of cerebral malaria (thrombocytopenia, herbal medicine, and intravascular hemolysis). Improved preventive and therapeutic measures may need to consider these differences.

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