Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium

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.