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Many tissue-resident macrophages are derived from embryonic precursors. Mowat and colleagues show that embryonic precursor cells seed gut tissues but at weaning transition to a bone marrow–derived macrophage population that requires continual replenishment. The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2–dependent influx of Ly6C hi monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool.

Key Points Chemokines regulate the infiltration of different immune cell subsets into tumours and, as such, these molecules affect tumour immunity and influence therapeutic outcomes in patients. Chemokines also target tumour cells and stromal cells, and they regulate tumour angiogenesis, stemness, proliferation and survival. Chemokine expression is regulated intrinsically by epigenetic and genetic pathways, and also extrinsically by hypoxia, metabolic cues and the microbiota. Targeting chemokine networks may alter tumour biological and immunological phenotypes, and increase antitumour immune responses. Therapies that target chemokines could synergize with existing cancer therapies, including current immunotherapies. This Review details how chemokines shape immune responses in the tumour microenvironment through their effects on immune cells, stromal cells and the tumour cells themselves. The authors discuss the potential of targeting chemokine networks for cancer therapy. The tumour microenvironment is the primary location in which tumour cells and the host immune system interact. Different immune cell subsets are recruited into the tumour microenvironment via interactions between chemokines and chemokine receptors, and these populations have distinct effects on tumour progression and therapeutic outcomes. In this Review, we focus on the main chemokines that are found in the human tumour microenvironment; we elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and we consider how they affect cancer immunity and tumorigenesis. We also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer.

Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood–brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b + antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity. Autoimmune brain inflammation is associated with activation of macrophages and microglia. Here the authors show that fibrinogen induces encephalitogenic T-cell activation and macrophage recruitment to the central nervous system, and promotes demyelination in a mouse model of multiple sclerosis.

Key Points Leukocyte migration is a central component of all physiological and pathological immune and inflammatory responses. Chemokines, functioning through conventional G protein-coupled chemokine receptors, are the key molecules that are involved in coordinating this process. Atypical chemokine receptors (ACKRs) are structurally related to conventional chemokine receptors but are unable to initiate classical chemokine receptor signalling after ligand binding. This family of chemokine receptors currently has four members: ACKR1 (also known as DARC), ACKR2 (also known as D6), ACKR3 (also known as CXCR7) and ACKR4 (also known as CCRL1). ACKRs use a variety of strategies to regulate chemokines and chemokine-driven responses, including chemokine degradation and transport, and chemokine receptor regulation. Endothelial cells of the lymphatic and blood vasculature are prominent sites of ACKR expression. Studies investigating genetic variation in human ACKRs and the effect of ACKR deficiency in mice and zebrafish have showed that some ACKRs have key developmental and homeostatic functions in the immune system and elsewhere. ACKRs have emerged as important regulators of immune and inflammatory responses, infectious disease, and cancer, and could represent plausible therapeutic targets. Chemokines control key immunological processes by signalling through G protein-coupled receptors. In addition, chemokines can be bound by atypical chemokine receptors (ACKRs), which are structurally related to conventional chemokine receptors, but which do not mediate classical signalling responses. This Review describes the biological functions of ACKRs and introduces the new nomenclature that has been proposed for this family. Chemokines have fundamental roles in regulating immune and inflammatory responses, primarily through their control of leukocyte migration and localization. The biological functions of chemokines are typically mediated by signalling through G protein-coupled chemokine receptors, but chemokines are also bound by a small family of atypical chemokine receptors (ACKRs), the members of which are unified by their inability to initiate classical signalling pathways after ligand binding. These ACKRs are emerging as crucial regulatory components of chemokine networks in a wide range of developmental, physiological and pathological contexts. In this Review, we discuss the biochemical and immunological properties of ACKRs and the potential unifying themes in this family, and we highlight recent studies that identify novel roles for these molecules in development, homeostasis, inflammatory disease, infection and cancer.

Leukocyte migration is a fundamental component of innate and adaptive immune responses as it governs the recruitment and localization of these motile cells, which is crucial for immune cell priming, effector functions, memory responses and immune regulation. This complex cellular trafficking system is controlled to a large extent via highly regulated production of secreted chemokines and the restricted expression of their membrane-tethered G-protein-coupled receptors. The activity of chemokines and their receptors is also regulated by a subfamily of molecules known as atypical chemokine receptors (ACKRs), which are chemokine receptor-like molecules that do not couple to the classical signalling pathways that promote cell migration in response to chemokine ligation. There has been a great deal of progress in understanding the biology of these receptors and their functions in the immune system in the past decade. Here, we describe the contribution of the various ACKRs to innate and adaptive immune responses, focussing specifically on recent progress. This includes recent findings that have defined the role for ACKRs in sculpting extracellular chemokine gradients, findings that broaden the spectrum of chemokine ligands recognized by these receptors, candidate new additions to ACKR family, and our increasing understanding of the role of these receptors in shaping the migration of innate and adaptive immune cells.This Review from Comerford and McColl discusses recent advances that have been made in understanding the biology of the atypical chemokine receptor (ACKR) family. The authors explain how these receptors interact with their ligands to shape immune responses and also highlight potential new additions to the ACKR family.

BK polyomavirus (PyV) establishes lifelong asymptomatic infections in the reno-urinary system of most humans. BKPyV-associated nephropathy is the leading infectious cause of kidney allograft loss. Using mouse PyV, a natural murine pathogen that also persists in the kidney, we define a dominant chemokine receptor-chemokine axis that directs T cell infiltration of the kidney. We found that CXCR6 was required for CD4 + and CD8 + T cells to be recruited to and retained in the kidney, respectively. Absence of CXCR6 impaired virus control in the kidney. The soluble form of CXCL16 was increased in kidneys of infected mice and in vivo CXCL16 neutralization reduced numbers of virus-specific CD8 + T cells infiltrating the kidney. In vivo administration of IL-12 upregulated CXCR6 expression on virus-specific CD8 + T cells, improved T cell recruitment to the infected kidney, and reduced virus levels. Notably, T cells in kidney biopsies from PyV-associated nephropathy patients express CXCR6 and transcriptional analysis shows significant upregulation of CXCR6 and CXCL16 . These findings demonstrate the importance of the CXCR6-CXCL16 axis in regulating T cell responses in the kidney to PyV infection.

Chemerin is a multifunctional adipokine with established roles in inflammation, adipogenesis and glucose homeostasis. Increasing evidence suggest an important function of chemerin in cancer. Chemerin’s main cellular receptors, chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) are expressed in most normal and tumor tissues. Chemerin’s role in cancer is considered controversial, since it is able to exert both anti-tumoral and tumor-promoting effects, which are mediated by different mechanisms like recruiting innate immune defenses or activation of endothelial angiogenesis. For this review article, original research articles on the role of chemerin and its receptors in cancer were considered, which are listed in the PubMed database. Additionally, we included meta-analyses of publicly accessible DNA microarray data to elucidate the association of expression of chemerin and its receptors in tumor tissues with patients’ survival.

Key Points Chemokine receptors are attractive therapeutic targets for inflammatory and autoimmune diseases. It is likely that chemokine receptors could be effectively targeted using small molecule inhibitors. Drugs targeting various chemokine receptors have been approved for non-inflammatory conditions, but so far there are no such drugs for autoimmune or inflammatory disease. The current lack of successful drugs targeting chemokine receptors in autoimmune and inflammatory diseases should not be attributed to the so-called 'redundancy' of the chemokine system. Successful chemokine receptor-based drugs will be enabled by understanding that target selection and sufficient receptor coverage are crucial for therapeutic efficacy. Clinical trials designed according to these principles will establish the validity of therapeutic interventions that inhibit this receptor class. Despite the frequently proposed 'redundancy' of the chemokine system, these authors put forward the opinion that targeting a single chemokine receptor can be effective in treating inflammatory disease provided that the in vivo potency is sufficient. Chemokines and their receptors are central to the inflammatory process and are attractive therapeutic targets. Drugs that inhibit chemokine receptors are approved for the treatment of HIV infection and for stem cell mobilization, but none have been approved yet for the treatment of inflammatory and/or autoimmune diseases. We analyse the challenges of developing chemokine receptor antagonists, and propose that inappropriate target selection and ineffective dosing, not the 'redundancy' of the chemokine system, are the main barriers to their use as anti-inflammatory therapies. We highlight evidence suggesting that chemokine receptor inhibition will prove to be an effective therapy in inflammatory diseases.

Atrophic age‐related macular degeneration (AMD) is associated with the subretinal accumulation of mononuclear phagocytes (MPs). Their role in promoting or inhibiting retinal degeneration is unknown. We here show that atrophic AMD is associated with increased intraocular CCL2 levels and subretinal CCR2 + inflammatory monocyte infiltration in patients. Using age‐ and light‐induced subretinal inflammation and photoreceptor degeneration in Cx3cr1 knockout mice, we show that subretinal Cx3cr1 deficient MPs overexpress CCL2 and that both the genetic deletion of CCL2 or CCR2 and the pharmacological inhibition of CCR2 prevent inflammatory monocyte recruitment, MP accumulation and photoreceptor degeneration in vivo . Our study shows that contrary to CCR2 and CCL2, CX3CR1 is constitutively expressed in the retina where it represses the expression of CCL2 and the recruitment of neurotoxic inflammatory CCR2 + monocytes. CCL2/CCR2 inhibition might represent a powerful tool for controlling inflammation and neurodegeneration in AMD. Graphical Abstract The eyes of patients with atrophic AMD feature high CCL2 and CCR2 + monocytes. This is modeled in Cx3cr1 KO mice in which Ccl2 and Ccr2 deletion, CCR2 inhibition and monocyte depletion diminished subretinal inflammation and photoreceptor degeneration.

Complement provides costimulatory signals to T cells. Medof and colleagues demonstrate that an absence of complement signaling in naive T cells generates an autoinductive loop to drive induced regulatory T cells. Signaling through the G protein–coupled receptors for the complement fragments C3a and C5a (C3aR and C5aR, respectively) by dendritic cells and CD4 + cells provides costimulatory and survival signals to effector T cells. Here we found that when signals from C3aR and C5aR were not transduced into CD4 + cells, signaling via the kinases PI(3)Kγ, Akt and mTOR ceased, activation of the kinase PKA increased, autoinductive signaling by transforming growth factor-β1 (TGF-β1) initiated and CD4 + T cells became Foxp3 + induced regulatory T cells (iT reg cells). Endogenous TGF-β1 suppressed signaling through C3aR and C5aR by preventing the production of C3a and C5a and upregulating C5L2, an alternative receptor for C5a. The absence of signaling via C3aR and C5aR resulted in lower expression of costimulatory molecules and interleukin 6 (IL-6) and more production of IL-10. The resulting iT reg cells exerted robust suppression, had enhanced stability and suppressed ongoing autoimmune disease. Antagonism of C3aR and C5aR can also induce functional human iT reg cells.