Hu Y, Ivashkiv LBCostimulation of chemokine receptor signaling by matrix metalloproteinase-9 mediates enhanced migration of IFN-alpha dendritic cells. J Immunol 176:6022-6033

Graduate Program in Neuroscience, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2006; 176(10):6022-33.
Source: PubMed


Type I IFNs induce differentiation of dendritic cells (DCs) with potent Ag-presenting capacity, termed IFN-alpha DCs, that have been implicated in the pathogenesis of systemic lupus erythematosus. In this study, we found that IFN-alpha DCs exhibit enhanced migration across the extracellular matrix (ECM) in response to chemokines CCL3 and CCL5 that recruit DCs to inflammatory sites, but not the lymphoid-homing chemokine CCL21. IFN-alpha DCs expressed elevated matrix metalloproteinase-9 (MMP-9), which mediated increased migration across ECM. Unexpectedly, MMP-9 and its cell surface receptors CD11b and CD44 were required for enhanced CCL5-induced chemotaxis even in the absence of a matrix barrier. MMP-9, CD11b, and CD44 selectively modulated CCL5-dependent activation of JNK that was required for enhanced chemotactic responses. These results establish the migratory phenotype of IFN-alpha DCs and identify an important role for costimulation of chemotactic responses by synergistic activation of JNK. Thus, cell motility is regulated by integrating signaling inputs from chemokine receptors and molecules such as MMP-9, CD11b, and CD44 that also mediate cell interactions with inflammatory factors and ECM.

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    • "T cells, in turn, can play important roles in augmenting alveolar macrophage derived MMP12 content of the lung (Maeno et al. 2007), a known contributor to emphysema development/severity (Chaudhuri et al. 2012). MMP-9, itself implicated in emphysema development (Yao et al. 2013), can be produced directly by pDCs (Hu and Ivashkiv 2006) thus supporting a possible direct mechanism. Further studies into pDC function and their clinical consequences in severe asthma and COPD are thus warranted. "
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    ABSTRACT: Patients with asthma and chronic obstructive pulmonary disease (COPD) are susceptible to exacerbations, often caused by microbial pathogens. We hypothesised that intracellular Toll-like receptor (TLR) function in blood mononuclear cells (PBMCs) from these subjects would be impaired and that this impairment is related to exacerbation frequency. PBMCs stimulated with a TLR-9 agonist (but not TLR-3 or 7/8) produced significantly less IFN-α in asthma (26 [3–696] pg/ml) compared to control (943 [164–1651]) and COPD (597 [127–1186]) subjects (p = 0.0019) but this was not related to the number of exacerbations per year in asthma or COPD. In COPD, IFN-α levels were related to KCO (% predicted) in COPD (r = -0.41, p = 0.01). IFN-α was derived from plasmacytoid dendritic cells (pDCs) and their frequency was lower in asthma compared to control subjects (Control 0.48% [0.33-0.64] vs asthma 0.29% [0.13-0.34], p = 0.019) whereas pDC function per se was not significantly impaired between groups. The mechanism underlying reduced IFN-α production and the clinical consequences in severe asthma remains to be established.
    Immunobiology 01/2015; 220(7). DOI:10.1016/j.imbio.2015.01.005 · 3.04 Impact Factor
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    • "We have also shown that the tight junction protein occludin is reorganized when DCs migrate across brain capillary endothelial cell monolayers, and DCs produce matrix metallopreintases (MMPs) 2 and 9 when cultured with brain endothelial cells. CCL3 is also required for upregulation of costimulatory markers on CNS-infiltrating DCs during murine viral encephalitis (Trifilo and Lane 2004) and both CCL5 and CCL3 promote secretion of matrix metalloproteinase (MMP9) by monocytes (Robinson et al. 2002) and pDCs (Hu and Ivashkiv 2006) in vitro. Interestingly, in our experiments DCs showed an activated phenotype upon migration, and migration could be abrogated by treatment with an MMP inhibitor (Zozulya et al. 2007). "
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    ABSTRACT: Dendritic cells (DCs) are a heterogeneous group of professional antigen presenting cells that lie in a nexus between innate and adaptive immunity because they recognize and respond to danger signals and subsequently initiate and regulate effector T-cell responses. Initially thought to be absent from the CNS, both plasmacytoid and conventional DCs as well as DC precursors have recently been detected in several CNS compartments where they are seemingly poised for responding to injury and pathogens. Additionally, monocyte-derived DCs rapidly accumulate in the inflamed CNS where they, along with other DC subsets, may function to locally regulate effector T-cells and/or carry antigens to CNS-draining cervical lymph nodes. In this review we highlight recent research showing that (a) distinct inflammatory stimuli differentially recruit DC subsets to the CNS; (b) DC recruitment across the blood-brain barrier (BBB) is regulated by adhesion molecules, growth factors, and chemokines; and (c) DCs positively or negatively regulate immune responses in the CNS.
    Advances in Experimental Medicine and Biology 01/2012; 946:309-33. DOI:10.1007/978-1-4614-0106-3_18 · 1.96 Impact Factor
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    • "Furthermore, MMP-9 supported the migration of DCs independent of an extracellular barrier (Hu and Ivashkiv, 2006). Hu and Ivashkiv (2006) showed that MMP-9 enhanced the CCL5-mediated signaling by a synergistic activation of JNK. Thus, MMP-9 may have an effect as a tuner and amplifier of immune functions by cleavage of matrix components and modification of cytokine and chemokine activity (Opdenakker et al., 2001b). "
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    ABSTRACT: Migration of dendritic cells (DCs) from skin to lymph nodes on activation is an essential step in the initiation of an adequate immune response. The dermal microenvironment including stromal cells and their soluble factors might be involved in the regulation of DC migration. To focus on the role of dermal fibroblasts, we studied whether interaction of DCs with fibroblasts promotes the migration of DCs. DCs were co-cultured with resting fibroblasts or with tumor necrosis factor (TNF)alpha/IL-1beta-activated fibroblasts to mimic an inflammatory microenvironment. Interaction of DCs with TNFalpha/IL-1beta-stimulated fibroblasts increased the secretion of matrix metalloproteinase-9 (MMP-9) from DCs within 6 hours compared with DCs alone or DCs stimulated with lipopolysaccharide or TNFalpha/IL-1beta. In contrast, unstimulated fibroblasts did not affect MMP-9 secretion. IL-6 released by TNFalpha/IL-1beta-stimulated fibroblasts was identified as a factor responsible for fibroblast-stimulated MMP-9 secretion from DCs. In accordance with the elevated MMP-9 release, on co-culture with TNFalpha/IL-1beta-stimulated fibroblasts, DCs migrated significantly more effectively through matrigel matrices than did TNFalpha/IL-1beta-stimulated DCs. This was inhibited by a selective blocking of MMP-9, indicating the importance of MMP-9 for this migratory capacity of DCs. In summary, fibroblasts in the local dermal microenvironment are capable of potentiating the migratory capacity of DCs, and thus have the potential to actively participate in the regulation of a cutaneous immune response.
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