Flavivirus infection induces indoleamine 2,3-dioxygenase in human monocyte-derived macrophages via tumor necrosis factor and NF-κB.
J Leukoc Biol. 2012 Feb 1;
Authors: Yeung AW, Wu W, Freewan M, Stocker R, King NJ, Thomas SR
Abstract
Infection with West Nile virus (WNV) via a mosquito bite results in local viral replication in the skin, followed by viremia. Thus, tissue macrophages are ideally located to prevent the dissemination of WNV throughout the host. The current study shows that WNV infection of human monocyte-derived macrophages (MDM) results in increased WNV mRNA, protein, and infectious virions at 24 h p.i. with a decline in titer after 48 h. Concomitant with viral control was the robust induction of indoleamine 2,3-dioxygenase (IDO) and resultant metabolism of L-tryptophan (L-Trp) to kynurenine. In WNV-exposed cultures, IDO protein was induced primarily in noninfected versus viral-infected MDM. Whereas WNV infection increased the production of IFN-α, IFN-β, and TNF, only antibody neutralization of TNF attenuated IDO expression and activity. WNV infection also activated NF-κB, and inhibition of this pathway with BMS-345541 abrogated IDO induction. Similar results were also obtained with MDM infected with the related flavivirus, Japanese encephalitis virus. Whereas IDO-mediated L-Trp metabolism can exhibit antiviral properties, inhibition of IDO activity in MDM with L-1-MT or the addition of excess L-Trp did not affect viral control. However, culturing MDM in L-Trp-deficient medium or overexpression of IDO in cells prior to infection significantly attenuated WNV replication, which was reversed by adding excess L-Trp. Together, these data support that although IDO is not required by MDM for the clearance of established viral infection, the spread of flavivirus infection is limited by IDO expressed in uninfected, neighboring cells.
PMID: 22301793 [PubMed - as supplied by publisher]
Platelet-activating factor receptor plays a role in the pathogenesis of graft-versus-host disease by regulating leukocyte recruitment, tissue injury, and lethality.
J Leukoc Biol. 2012 Feb 1;
Authors: Castor MG, Rezende BM, Resende CB, Bernardes PT, Cisalpino D, Vieira AT, Souza DG, Silva TA, Teixeira MM, Pinho V
Abstract
PAF is a potent lipid mediator involved in several manifestations of acute inflammation, including leukocyte influx, leukocyte interaction with endothelium, and production of inflammatory cytokines. The present study evaluated the relevance of PAFR for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PAFR(-/- )C57BL/6J to B6D2F1 mice. Mice, which received PAFR(-/- )splenocytes or treatment with the PAFR antagonist, showed reduced clinical signs of disease and no mortality. In GVHD mice receiving PAFR(-/-) splenocytes, there was deceased bacterial translocation and tissue injury. Furthermore, production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and accumulation of CD8(+) cells in intestine and liver were reduced in mice transplanted with the PAFR(-/-) splenocyte. Mechanistically, an absence or pharmacological blockade of PAFR was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PAFR(-/-) leukocytes were transferred into WT mice. In conclusion, PAFR on donor leukocytes plays a critical role in GVHD by mediating leukocyte influx and cytokine production in target tissues. PAFR antagonist may potentially be useful in the treatment of GVHD in bone marrow-transplanted patients.
PMID: 22301794 [PubMed - as supplied by publisher]
Migration of monocytes after intracerebral injection at entorhinal cortex lesion site.
J Leukoc Biol. 2012 Jan 30;
Authors: Kaminski M, Bechmann I, Pohland M, Kiwit J, Nitsch R, Glumm J
Abstract
The lack of classical lymph vessels within brain tissue complicates immune surveillance of the CNS, and therefore, cellular emigration out of the CNS parenchyma requires alternate pathways. Whereas invasion of blood-derived mononuclear cells and their transformation into ramified, microglia-like cells in areas of axonal degeneration across an intact BBB have been demonstrated, it still remained unclear whether these cells reside permanently, undergo apoptosis, or leave the brain to present antigen in lymphoid organs. With the use of ECL of mice and injection of GFP-expressing monocytes, we followed the appearance of injected cells in spleen and LNs and the migratory pathways in whole-head histological sections. Monocytes migrated from the lesion site to deep CLNs, peaking in number at Day 7, but they were virtually absent in spleen and in superficial CLNs and inguinal LNs until Day 21 after lesion/injection. In whole-head sections, GFP monocytes were found attached to the olfactory nerves and located within the nasal mucosa at 48 hpi. Thus, monocytes are capable of migrating from lesioned brain areas to deep CLNs and use the cribriform plate as an exit route.
PMID: 22291210 [PubMed - as supplied by publisher]
Donor-derived, tolerogenic dendritic cells suppress immune rejection in the indirect allosensitization-dominant setting of corneal transplantation.
J Leukoc Biol. 2012 Jan 30;
Authors: Hattori T, Saban DR, Emami-Naeini P, Chauhan SK, Funaki T, Ueno H, Dana R
Abstract
Significant interest has been focused on the use of ex vivo-manipulated DCs to optimally induce transplant tolerance and promote allograft survival. Although it is understood that donor-derived, tolerogenic DCs suppress the direct pathway of allosensitization, whether such DCs can similarly suppress the indirect pathway remains unclear. We therefore used the murine model of corneal transplantation to address this, as these allografts are rejected in an indirect pathway-dominant manner. Interestingly, recipients administered with donor bone marrow-derived DCregs, generated via culturing with GM-CSF, IL-10, and TGF-β1, significantly prolonged survival of corneal allografts. Correspondingly, these recipients demonstrated a potent reduction in the frequency of indirectly allosensitized T cells, as determined by ELISPOT. Examination of DCregs relative to mDCs or iDCs showed a resistance to up-regulation of MHC-II and costimulatory molecules, as well as an impaired capacity to stimulate MLRs. In vivo, DCreg administration in corneal-allografted recipients led to inhibition of CD4(+)IFN-γ(+) T cell frequencies and an associated increase in Foxp3 expression in the Treg compartment. We conclude that donor-derived, tolerogenic DCs significantly suppress the indirect pathway, thereby identifying a novel regulatory mechanism for these cells in transplantation.
PMID: 22291211 [PubMed - as supplied by publisher]
Emerging roles of pulmonary macrophages in driving the development of severe asthma.
J Leukoc Biol. 2012 Jan 31;
Authors: Yang M, Kumar RK, Hansbro PM, Foster PS
Abstract
Asthma is recognized as a heterogeneous disorder, although in most patients, the clinical manifestations are effectively managed with established combination therapies. However, 5-10% of asthmatics have severe asthma, which does not respond to treatment, and these patients account for >50% of asthma-related healthcare costs. New investigations into the pathogenesis of glucocorticoid resistance in severe asthma indicate that pulmonary macrophages may play central roles in promoting airway inflammation, particularly in asthma that is resistant to steroid therapy. Importantly, factors that are linked to the activation of pulmonary macrophages may contribute to glucocorticoid resistance and severe asthma. Here, we review recent advances in understanding the roles of pulmonary macrophages in the mechanisms of glucocorticoid resistance and the pathogenesis of severe asthma. We discuss the role of macrophage phenotype, infection, IFN-γ, LPS, associated signaling pathways, TNF-α, MIF, and other macrophage-associated factors. Understanding the pathogenesis of steroid-resistant severe asthma will contribute to the identification of optimal therapeutic strategies for the effective management of the disease.
PMID: 22293472 [PubMed - as supplied by publisher]
Reprogramming of TAM toward proimmunogenic type through regulation of MAP kinases using a redox-active copper chelate.
J Leukoc Biol. 2012 Jan 25;
Authors: Chakraborty P, Chatterjee S, Ganguly A, Saha P, Adhikary A, Das T, Chatterjee M, Choudhuri SK
Abstract
TAMs, present in the tumor microenvironment, play an immunosuppressive role, leading to tumor progression and metastasis. Recently, numerous attempts have been made to switch immunosuppressive TAMs into an immunostimulatory type. Previously, we showed that a copper chelate, viz., copper N-(2-hydroxy acetophenone) glycinate [CuNG], can reprogram TAMs toward the proimmunogenic type to mount an antitumor immune response, but the underlying molecular mechanisms of skewing TAMs toward the proimmunogenic type remain elusive. Herein, we tried to explore the signaling mechanisms responsible for the reprogramming of TAMs. We observed that CuNG-induced ROS generation triggers activation of two MAPKs, i.e., p38MAPK and ERK1/2, and also causes up-regulation of intracellular glutathione. Furthermore, activation of p38 MAPK up-regulated the initial IL-12 production and the activation of ERK1/2 in tandem with GSH, found responsible for IFN-γ production by TAMs. This IFN-γ, in turn, prolonged IL-12 production and down-regulated TGF-β production and thus, plays the decisive role in CuNG-mediated reprogramming of regulatory cytokine production by TAMs. Our work highlights that ROS-mediated activation of MAPKs can convert suppressive macrophages toward the proimmunogenic type. Thus, the present study opens the possibility of targeting TAMs by the use of redox-active compounds for designing a novel, therapeutic strategy against cancer.
PMID: 22279179 [PubMed - as supplied by publisher]
Peritoneal macrophage from male and female SJL mice differ in IL-10 expression and macrophage maturation.
J Leukoc Biol. 2012 Jan 18;
Authors: Hussain S, Stohlman SA
Abstract
Injection of proteins and particulate antigens into the peritoneal cavity of male SJL mice preferentially activates T cells secreting Th2 cytokines. Identical immunizations of females activate T cells secreting Th1 cytokines. CD11b(+)F4/80(hi) LPM and CD11b(+)F4/80(lo) SPM populations were compared between naive males and females to define their role in supporting differential Th1 versus Th2 T cell activation. No sex-dependent differences in the expression of MHC class II, costimulatory molecules, and MR were detected. Immunization induced influx of CD11b(lo)F4/80(lo) cells in both sexes. CD11b(lo)F4/80(lo) cells consist predominantly of Ly6C(hi) monocytes, which mature into a Ly6C(-) SPM subset. Following immunization, equivalent frequencies of LPM had taken up antigen. However, the CD11b(lo)F4/80(lo) population, which had taken up antigen, was decreased significantly in males compared with females. Similar to naïve macrophages, antigen-positive cells in immunized males and females exhibited no phenotypic differences. However, fewer Ly6C(-)F4/80(+) cells were present in males compared with females, consistent with the reduced number of antigen-positive cells. Furthermore, CD11b(lo)F4/80(lo) cells, which had taken up antigen in males, expressed increased IL-10 and limited IL-12 mRNA compared with the predominant IL-12 mRNA expression in female-derived, antigen-positive CD11b(lo)F4/80(lo) cells. IL-10 blockade increased the frequency of Ly6C(-)F4/80(+) cells in males to the frequency in females, suggesting that preferential activation of Th2 T cells in male SJL mice is associated with increased IL-10 expression and limited antigen presentation as a result of decreased macrophage maturation under the influence of IL-10.
PMID: 22262797 [PubMed - as supplied by publisher]
Microenvironmental regulation of inducible nitric oxide synthase expression and nitric oxide production in mouse bone marrow-derived mast cells.
J Leukoc Biol. 2012 Jan 18;
Authors: Moon TC, Yoshimura T, Parsons T, Befus AD
Abstract
In addition to its well-known role in relaxation of vascular smooth muscle, NO modulates immune responses in a concentration- and location-specific manner. For MC, it is well accepted that exogenous NO regulates their function. However, there are inconsistencies in the literature of whether MC express NOS and make NO. MC progenitors mature in peripheral tissues, but the factors that influence MC maturation and their specific phenotype, such as whether they express NOS, are not well understood. To study microenvironmental conditions that could be “permissive” for NOS expression, we cultured BMMC in various conditions-BMMC(IL-3), BMMC(SCF/IL-3), or BMMC(SCF/IL-4)-for >3 weeks and examined NOS expression. We detected Nos2 mRNA in BMMC(SCF/IL-4) but not BMMC(IL-3) or BMMC(SCF/IL-3). After stimulation with IFN-γ and/or LPS, NOS2 expression and NO production were detected in BMMC(SCF/IL-4) but rarely detected in BMMC cultured with other conditions. Confocal microscopic analysis showed that NOS2 expression induced by IFN-γ colocalized in CD117(+) BMMC. NO production, after activation with IFN-γ and LPS in BMMC(SCF/IL-4), was abrogated by pretreatment with the NOS2-specific inhibitor. In addition to NOS2 expression, BMMC(SCF/IL-4) were distinguished from BMMC(IL-3) in heparin and MMCP expression. Thus, MC progenitors that develop in SCF + IL-4 can be induced to express NOS2 after receiving appropriate signals, such as IFN-γ, and subsequently produce NO. Microenvironmental conditions during their development can influence whether MC are capable of NOS expression and of NO production.
PMID: 22262798 [PubMed - as supplied by publisher]
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