Crosstalk between Sentinel and Helper Macrophages Permits Neutrophil Migration into Infected Uroepithelium

Abstract

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.

Similar Neutrophil-Driven Inflammatory and Antibacterial Responses in Elderly Patients with Symptomatic and Asymptomatic Bacteriuria

“…The observation of pyuria (leukocyte counts of Ն4 or 10 per HPF in urine) implicates the infiltration of activated neutrophils as the main drivers of the acute immune response in UTIs (19). Urothelial cells and macrophages contribute to the release of proinflammatory and antibacterial molecules and amplify the host defense in the urinary tract (20,37). It has not been investigated in studies on clinical samples, to our knowledge, whether these immune responses involve a range of neutrophil effectors to similar degrees in cases of UTI caused by different pathogens and whether the responses functionally and quantitatively differ in patients diagnosed with ASB.…”

Cryopreserved Interleukin-4-Treated Macrophages Attenuate Murine Colitis in an Integrin β7-Dependent Manner

“…The concept of macrophage-macrophage interaction is not unprecedented (32), and it was intriguing to consider the possibility that the therapeutic benefit of adoptive transfer of M(IL-4)s could be amplified by co-opting macrophages in the recipient mice. By using clodronate-filled liposomes to deplete macrophages (minor effects on neutrophils and dendritic cells have been described with this technique [25]), it was found that peritoneal macrophages healing via effects on epithelial cells or fibroblasts (11).…”

Dendritic Cells and Macrophages

“…By contrast, the defense against bacterial cystitis entirely depended on macrophages (more exactly on the interplay between two functionally distinct macrophage subsets that can be distinguished by expression of the Ly6C marker) (16) (Figure 4B). Bladder-resident Ly6C 2 sentinel macrophages performed a role comparable with the role of DCs in the kidney: they sensed the infection and produced chemokines that recruited neutrophils and Ly6C 1 monocytes.…”

“…However, these functions seem to represent merely two ends of a broad spectrum of macrophage polarization states (15). Another classification system uses the Ly6C marker to distinguish inflammatory and tissue-resident macrophages, which seem to perform distinct tasks in the anti-infectious defense (16,17). This difference is also evident in blood monocytes: in addition to the classic Ly6C 1 inflammatory monocytes that are dependent on the chemokine receptor CCR2, a distinct subset of Ly6C 2 monocytes expressing high levels of the chemokine receptor CX 3 CR1 has been described (18).…”