Macrophage origin limits functional plasticity in helminth-bacterial co-infection

Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell

Shining light on integrity of a tetracobalt polyoxometalate water oxidation catalyst by X ray spectroscopy before and after catalysis

Modification of the Co-oxo cores of cobalt-polyoxometalate water oxidation catalysts is detectable by X-ray absorption spectroscopy (XAS) as demonstrated by comparison of Na10[Co4(H2O)2(PW9O34)2] (1) and Na17[((Co(H2O))Co2PW9O34)2(PW6O26)] (2). XAS reveals the integrity of 1 uncompromised by oxidant-driven water oxidation, which proceeds without formation of catalytic cobalt oxide

T helper type 1 memory cells disseminate postoperative ileus over the entire intestinal tract

Localized abdominal surgery can lead to disruption of motility in the entire gastrointestinal tract (postoperative ileus). Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how the macrophages are activated, especially those in unmanipulated intestinal areas. Here we show that intestinal surgery activates intestinal CD103(+)CD11b(+) dendritic cells (DCs) to produce interleukin-12 (IL-12). This promotes interferon-γ (IFN-γ) secretion by CCR9(+) memory T helper type 1 (T(H)1) cells which activates the macrophages. IL-12 also caused some T(H)1 cells to migrate from surgically manipulated sites through the bloodstream to unmanipulated intestinal areas where they induced ileus. Preventing T cell migration with the drug FTY720 or inhibition of IL-12, T-bet (T(H)1-specific T box transcription factor) or IFN-γ prevented postoperative ileus. CCR9(+) T(H)1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a T(H)1 immune-mediated disease and identify potential targets for disease monitoring and therap

T helper type 1 memory cells disseminate postoperative ileus over the entire intestinal tract

Localized abdominal surgery can lead to disruption of motility in the entire gastrointestinal tract (postoperative ileus). Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how the macrophages are activated, especially those in unmanipulated intestinal areas. Here we show that intestinal surgery activates intestinal CD103(+)CD11b(+) dendritic cells (DCs) to produce interleukin-12 (IL-12). This promotes interferon-γ (IFN-γ) secretion by CCR9(+) memory T helper type 1 (T(H)1) cells which activates the macrophages. IL-12 also caused some T(H)1 cells to migrate from surgically manipulated sites through the bloodstream to unmanipulated intestinal areas where they induced ileus. Preventing T cell migration with the drug FTY720 or inhibition of IL-12, T-bet (T(H)1-specific T box transcription factor) or IFN-γ prevented postoperative ileus. CCR9(+) T(H)1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a T(H)1 immune-mediated disease and identify potential targets for disease monitoring and therap

Structural and functional studies on ø29 DNA polymerase

The Bac i l lus subtilis phage 029 DNA polymerase, involved in protein-primed viral DNA repli- cation, contains several amino acid consensus sequences common to other eukaryotic-type DNA polymerases. Us- ing site-directed mutagenesis, we have studied the func- tional significance o f a C-terminal conserved region, rep- resented by the Lys-X-Tyr ("K-Y") motif. Single point mutants have be en constructed and the corresponding proteins have been overproduced and characterized. Measurements o f the activity o f the mutant proteins indi- cated that the invariant Lys and Tyr residues play a criti- cal role in DNA polymerization. Interestingly, substitu- tion o f the invariant Lys either by Arg or Thr, produced enzymes with an increased or a largely reduced, respec- tively, capability to use a protein as primer, an intrinsic property o f TP-priming DNA polymerases. On the other hand, the viral protein p6, whi ch stimulates initiation o f 029 DNA replication by formation o f a nucleoprotein complex at both DNA replication origins, increased (about 5-fold) the insertion fidelity o f 029 DNA polymerase during the formation o f the TP-dAMP initia- tion complex. We propose a mode l in whi ch the special strategy to maintain the integrity o f the 029 DNA ends, by means o f a "sliding-back" mechanism, could also con- tribute to increase the fidelity o f 029 DNA replication.This investigation has been aided byreseareh grant 5R01 GM27242-13 from the National Institutes o f Health, by grant n ~ PB90-0091 from Direccibn General de Investigacibn Cientifica y T6c- nica, by grant BlOT CT 91-0268 from European Economic Commani- ty, and by an institutional grant from Fundaci6n Ram6n Areces. M.A.B., J.A.E. and J.M., were predoctoral fellows from Ministerio de Educaci6n y Ciencia.Peer reviewe

Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium

The phagocytes of the innate immune system, macrophages and neutrophils, contribute to antibacterial defense, but their functional specialization and cooperation is unclear. Here, we report that three distinct phagocyte subsets play highly coordinated roles in bacterial urinary tract infection. Ly6C(-) macrophages acted as tissue-resident sentinels that attracted circulating neutrophils and Ly6C(+) macrophages. Such Ly6C(+) macrophages played a previously undescribed helper role: once recruited to the site of infection, they produced the cytokine TNF, which caused Ly6C(-) macrophages to secrete CXCL2. This chemokine activated matrix metalloproteinase-9 in neutrophils, allowing their entry into the uroepithelium to combat the bacteria. In summary, the sentinel macrophages elicit the powerful antibacterial functions of neutrophils only after confirmation by the helper macrophages, reminiscent of the licensing role of helper T cells in antiviral adaptive immunity. These findings identify helper macrophages and TNF as critical regulators in innate immunity against bacterial infections in epithelia.publisher: Elsevier articletitle: Crosstalk between Sentinel and Helper Macrophages Permits Neutrophil Migration into Infected Uroepithelium journaltitle: Cell articlelink: http://dx.doi.org/10.1016/j.cell.2014.01.006 content_type: article copyright: Copyright © 2014 Elsevier Inc. All rights reserved.status: publishe