CCRL2 is a 7-transmembrane domain receptor that shares structural and functional similarities with the family of atypical chemokine receptors (ACKRs). CCRL2 is upregulated by inflammatory signals and, unlike other ACKRs, it is not a chemoattractant-scavenging receptor, does not activate β-arrestins, and is widely expressed by many leukocyte subsets. Therefore, the biological role of CCRL2 in immunity is still unclear. We report that CCRL2-deficient mice have a defect in neutrophil recruitment and are protected in 2 models of inflammatory arthritis. In vitro, CCRL2 was found to constitutively form homodimers and heterodimers with CXCR2, a main neutrophil chemotactic receptor. By heterodimerization, CCRL2 could regulate membrane expression and promote CXCR2 functions, including the activation of β2-integrins. Therefore, upregulation of CCRL2 observed under inflammatory conditions is functional to finely tune CXCR2-mediated neutrophil recruitment at sites of inflammation.
IntroductionHematopoiesis is a dynamic process in which multipotent, hematopoietic stem cells (HSCs) give rise to all hematopoietic lineage cells: neutrophils, eosinophils, basophils, monocytes, macrophages, megakaryocytes, platelets, and erythrocytes, which constitute the myeloid lineage, and T and B cells, which compose the lymphoid lineage. 1 After birth, sustained hematopoiesis in the bone marrow depends on the self-renewal of the resident HSCs in the stem cell niche, where signaling molecules, extracellular matrix (ECM), and cell adhesion molecules that regulate stem cell fates are produced. Indeed, hematopoiesis involves the coordination of several signal transduction pathways, which are induced by extracellular stimuli through cell-cell and cell-ECM interactions. 2 Among ECM components, heparan sulfate proteoglycans (HSPGs) are crucial controllers of the structural and functional organization of the bone marrow HSC niche, 3 where they regulate skeletalhematopoietic interactions 4 by mediating cell adhesion of hematopoietic progenitors to stromal cells 5 and by binding and thus modulating the activity of cytokines. 6 Agrin, an ECM protein belonging to the heterogeneous family of HSPGs expressed by motor neurons, is a critical regulator of neuromuscular synapses where it binds to skeletal muscle Lrp4, leading to activation of Musk, a receptor tyrosine kinase essential for transmitting the agrin signal. 7 However, the function of nonneuronal isoforms of agrin, expressed in numerous cell types, is poorly understood. Previous studies indicated a role for agrin at the T-cell immunologic synapse with antigen presenting cells. 8 The agrin receptor at the immunologic synapse has been defined as ␣-dystroglycan (␣-DG), 9 a broadly expressed cell surface receptor with a high affinity for ECM proteins. 10 Dystroglycans are critical in the early stages of development and mice deficient for ␣-DG show embryonic lethality at embryonic day (E) 6.5, probably arising from defects in extra-embryonic structures and their association with the extracellular matrix. 11 Interestingly, ␣-DG is expressed in human hematopoietic CD34 ϩ cells, 12 but the in vivo functional significance of such expression has not been determined. Here, we examined the role of agrin in postnatal hematopoiesis and found that agrin is a nonredundant component of the osteoblast endosteal niche providing signals essential for HSC survival. Methods MiceAgrin-deficient mice have been described elsewhere. 13 Musk-LAgrn ϩ/Ϫ mice (on C57BL/6 background) were bred at the animal facility of the Humanitas Clinical Institute. Mutant and control mice were genotyped by PCR of tail DNA as already described. 13 Congenic B6(CD45.1) mice, purchased from The Jackson Laboratory, were maintained in the Charles River animal facility and used as recipients of bone marrow (BM) transplantation experiments. Congenic B6(CD45.2) mice were crossed with B6(CD45.1) mice to obtain B6(CD45.1/45.2) recipients for competition BM transfer experiments. Procedures involving animals and their ...
Specific surface proteins of Neisseria meningitidis have been proposed to stimulate leukocytes during tissue invasion and septic shock. In this study, we demonstrate that the adhesin N. meningitidis Adhesin A (NadA) involved in the colonization of the respiratory epithelium by hypervirulent N. meningitidis B strains also binds to and activates human monocytes/macrophages. Expression of NadA on the surface on Escherichia coli does not increase bacterial-monocyte association, but a NadA-positive strain induced a significantly higher amount of TNF-alpha and IL-8 compared with the parental NadA-negative strain, suggesting that NadA has an intrinsic stimulatory action on these cells. Consistently, highly pure, soluble NadA(Delta351-405), a proposed component of an antimeningococcal vaccine, efficiently stimulates monocytes/macrophages to secrete a selected pattern of cytokines and chemotactic factors characterized by high levels of IL-8, IL-6, MCP-1, and MIP-1alpha and low levels of the main vasoactive mediators TNF-alpha and IL-1. NadA(Delta351-405) also inhibited monocyte apoptosis and determined its differentiation into a macrophage-like phenotype.
These results show that platelets, which have a large repertoire of TLRs and IL-1 receptors, express high levels of IL-1R8, which plays a non-redundant function as a regulator of thrombocyte activity in vitro and in vivo.
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