Efficient clearance of apoptotic cells seems to be a prerequisite to prevent the development of autoimmunity. Here we identify that macrophage colony-stimulating factor (M-CSF)-driven macrophages (Mø2s) are potent phagocytes that have the unique capacity to preferentially bind and ingest early apoptotic cells. This macrophage subset has intrinsic anti-inflammatory properties, characterized by high interleukin-10 (IL-10) production in the absence of proinflammatory cytokines, such as IL-6 and tumor necrosis factor-␣ (TNF-␣). Importantly, whereas the IL-6 and TNF-␣ production by granulocyte-macrophage (GM)-CSF-driven macrophages (Mø1s) is inhibited upon uptake of apoptotic cells, the anti-inflammatory status of Mø2 is retained during phagocytosis. Mø2s were shown to use CD14 to tether apoptotic cells, whereas recognition of phosphatidylserine ( IntroductionDuring normal homeostasis and tissue turnover large numbers of cells undergoing apoptosis are promptly removed and replaced. The removal of apoptotic material plays an important role in the suppression of inflammation and the regulation of immune responses. [1][2][3] Apoptotic cells are a rich source of autoantigens, 4 which are involved in the physiologic maintenance of self-tolerance. The uptake and processing of apoptotic cells has been proposed to be a silent process, meaning that release of pro-inflammatory cytokines by phagocytes is prevented. [5][6][7][8] Impaired clearance of apoptotic cells, resulting in an accumulation of late apoptotic and secondary necrotic cells, might provide a danger signal to antigen-presenting cells (APCs), thus activating autoreactive T cells, and finally leading to the breakdown of peripheral tolerance. 3 Accumulating evidence has been provided that defective clearance of apoptotic cells can lead to exacerbation of inflammation and predisposes to the development of autoimmunity, such as in systemic lupus erythematosus (SLE). 9 The apoptotic cell clearance machinery includes professional phagocytes (ie, immature dendritic cells [DCs] and macrophages [Møs]), and nonprofessional phagocytes, including epithelial cells, fibroblasts, and mesangial cells. 10 It has become clear that there are various subsets in both DCs and Møs. [11][12][13] Recent in vitro data show that Møs can be polarized into proinflammatory (Mø1) and anti-inflammatory (Mø2) cells by granulocyte-macrophage colonystimulating factors (GM-CSFs) and M-CSFs (also called CSF-1), respectively. 14,15 Classically, GM-CSF and M-CSF are thought to be the primary growth factors for the differentiation of macrophages. 16 Mice lacking M-CSF develop a general Mø deficiency,17 whereas GM-CSF knockout mice showed no major deficiency of Mø. 18,19 In humans, M-CSF, but not GM-CSF, is an ubiquitous cytokine circulating in the human body. 14,20 Thus, M-CSF could be the default cytokine to drive Mø differentiation under steady-state conditions.The removal of apoptotic cells is an ongoing and constitutive process. Apoptotic cells provide "eat me" signals to phagocytes to promptly an...
Cells that undergo apoptosis or necrosis are promptly removed by phagocytes. Soluble opsonins such as complement can opsonize dying cells, thereby promoting their removal by phagocytes and modulating the immune response. The pivotal role of the complement system in the handling of dying cells has been demonstrated for the classical pathway (via C1q) and lectin pathway (via mannose-binding lectin and ficolin). Herein we report that the only known naturally occurring positive regulator of complement, properdin, binds predominantly to late apoptotic and necrotic cells, but not to early apoptotic cells. This binding occurs independently of C3b, which is additional to the standard model wherein properdin binds to preexisting clusters of C3b on targets and stabilizes the convertase C3bBb. By binding to late apoptotic or necrotic cells, properdin serves as a focal point for local amplification of alternative pathway complement activation. Furthermore, properdin exhibits a strong interaction with DNA that is exposed on the late stage of dying cells. Our data indicate that direct recognition of dying cells by properdin is essential to drive alternative pathway complement activation.
Ischemia/reperfusion injury (IRI) is a central phenomenon in kidney transplantation and AKI. Integrity of the renal peritubular capillary network is an important limiting factor in the recovery from IRI. facilitates vascular regeneration by functioning as an angiomiR and by modulating mobilization of hematopoietic stem/progenitor cells. We hypothesized that overexpression of miR-126 in the hematopoietic compartment could protect the kidney against IRI via preservation of microvascular integrity. Here, we demonstrate that hematopoietic overexpression of miR-126 increases neovascularization of subcutaneously implanted Matrigel plugs in mice. After renal IRI, mice overexpressing miR-126 displayed a marked decrease in urea levels, weight loss, fibrotic markers, and injury markers (such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). This protective effect was associated with a higher density of the peritubular capillary network in the corticomedullary junction and increased numbers of bone marrow-derived endothelial cells. Hematopoietic overexpression of miR-126 increased the number of circulating Lin 2 /Sca-1 + /cKit + hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin 2 /Sca-1 + /cKit + cells in the bone marrow and increased renal expression of its ligand stromal cell-derived factor 1, thus favoring mobilization of Lin 2 /Sca-1 + /cKit + cells toward the kidney. Taken together, these results suggest overexpression of miR-126 in the hematopoietic compartment is associated with stromal cell-derived factor 1/CXCR4-dependent vasculogenic progenitor cell mobilization and promotes vascular integrity and supports recovery of the kidney after IRI.
Deficiency of mannose-binding lectin (MBL), a recognition molecule of the lectin pathway of complement, is associated with increased susceptibility to infections. The high frequency of MBL deficiency suggests that defective MBL-mediated innate immunity can be compensated by alternative defense strategies. To examine this hypothesis, complement activation by MBL-binding ligands was studied. The results show that the prototypic MBL ligand mannan can induce complement activation via both the lectin pathway and the classical pathway. Furthermore, antibody binding to mannan restored complement activation in MBLdeficient serum in a C1q-dependent manner. Cooperation between the classical pathway and the lectin pathway was also observed for complement activation by protein 60 from Listeria monocytogenes. MBL pathway analysis at the levels of C4 and C5b-9 in the presence of classical pathway inhibition revealed a large variation of MBL pathway activity, depending on mbl2 gene polymorphisms. MBL pathway dysfunction in variant allele carriers is associated with reduced MBL ligand binding and a relative increase of low-molecular-mass MBL. These findings indicate that antibody-mediated classical pathway activation can compensate for impaired target opsonization via the MBL pathway in MBL-deficient individuals, and imply that MBL deficiency may become clinically relevant in absence of a concomitant adaptive immune response.
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