Yoshitaka Kimura

Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses

The eradication of tumor cells requires communication to and signaling by cells of the immune system. Natural killer (NK) cells are essential tumor-killing effector cells of the innate immune system; however, little is known about whether or how other immune cells recognize tumor cells to assist NK cells. Here, we show that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express N-glycan structures at high levels. Receptor recognition of these tumor cells causes the activation of the IRF5 transcription factor and downstream gene induction for the full-blown tumoricidal activity of NK cells. Consistent with this, we show exacerbated in vivo tumor growth in mice genetically deficient in either Dectin-1 or IRF5. The critical contribution of Dectin-1 in the recognition of and signaling by tumor cells may offer new insight into the anti-tumor immune system with therapeutic implications. DOI: http://dx.doi.org/10.7554/eLife.04177.001

Inflammasome activation in response to dead cells and their metabolites.

Cell death cannot go unnoticed. It demands that the surrounding cells clear away the corpses in a manner appropriate to the type of cell death. Dying cells represent a threat to the body that should be eliminated by the host immune response. Inflammasome activation followed by IL-1alpha release and IL-1beta maturation is crucial for tackling pathological conditions, including infections, whereas inflammasome activation precedes inflammatory pyroptotic cell death. On the other hand, recent studies have shown that the inflammasome plays an important role in the pathogenesis of metabolic diseases, including obesity, diabetes, and atherosclerosis. Here, we review current knowledge of the association between cell death, excess metabolites, and inflammasome activation as it relates to chronic inflammatory diseases.

PGE2 induced in and released by dying cells functions as an inhibitory DAMP

Significance Inflammation is an integral part of the immune responses for the protection of the host to harmful stimuli. However, because inflammation can also underlie the initiation and/or exacerbation of a variety of diseases, it must be tightly regulated. Upon cell death, self-derived molecules, called damage-associated molecular patterns (DAMPs), are released to activate inflammatory responses. It has been unknown whether inhibitory molecules are also released to balance the magnitude of the inflammatory responses. In this study, biochemical and in vivo data demonstrate that prostaglandin E2 is a DAMP that negatively regulates cell death-induced inflammatory responses. These findings reveal an unprecedented facet in the regulation of inflammation via the combined activity of activating and inhibiting DAMPs, which may have clinical implications. Cellular components released into the external milieu as a result of cell death and sensed by the body are generally termed damage-associated molecular patterns (DAMPs). Although DAMPs are conventionally thought to be protective to the host by evoking inflammatory responses important for immunity and wound repair, there is the prevailing notion that dysregulated release of DAMPs can also underlie or exacerbate disease development. However, the critical issue for how resultant DAMP-mediated responses are regulated has heretofore not been fully addressed. In the present study, we identify prostaglandin E2 (PGE2) as a DAMP that negatively regulates immune responses. We show that the production of PGE2 is augmented under cell death-inducing conditions via the transcriptional induction of the cyclooxygenase 2 (COX2) gene and that cell-released PGE2 suppresses the expression of genes associated with inflammation, thereby limiting the cell’s immunostimulatory activities. Consistent with this, inhibition of the PGE2 synthesis pathway potentiates the inflammation induced by dying cells. We also provide in vivo evidence for a protective role of PGE2 released upon acetaminophen-induced liver injury as well as a pathogenic role for PGE2 during tumor cell growth. Our study places this classically known lipid mediator in an unprecedented context—that is, an inhibitory DAMP vis-à-vis activating DAMPs, which may have translational implications for designing more effective therapeutic regimens for inflammation-associated diseases.

New Anomalous Phenomena in NMR Absorption and Spin Lattice Relaxation of Solid Hydrogen

NMR line shape and spin lattice relaxation time of solid hydrogen are measured at 22 MHz for the fractional ortho content of 0.55> X >0.08 and temperature range of 1 K> T >0.2 K. As the sample temperature decreases below 0.35 K, the absorption line changes from singlet to doublet. The phenomenon is observed at ortho contents as small as 0.08. The critical temperature ( T * ), below which the line exhibits the doublet structure, weakly depends on X and is expressed as T * =(0.3±0.1)( X +0.5) K (0.55> X >0.08). The spin lattice relaxation time ( T 1 ) is found to show an anomalous increase by a factor of 10 2 at T ≃ T * . The increase of T 1 with decreasing temperature below T * gives Δ L =0.25±0.05 K for the lower edge of the excited state with J z =±1. Temperature dependence of the field separation of the doublet line is analyzed by using the order parameter formulated by Ueyama and Matsubara. The result gives Δ =1.0±0.2 K for the mean energy gap between the rotational substate with J z =0 and J z =±1.

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis.

Significance The liver is a common site for metastatic disease, and liver metastasis is strongly correlated with poor prognosis. Therefore, an understanding of how liver metastasis is regulated by the immune system is one of the most important issues in cancer immunology. Liver-resident immune cells may either suppress or promote liver metastasis. In this study, we show that Dectin-2 and macrophage C-type lectin, both of which belong to the C-type lectin family of innate receptors, is expressed on resident liver macrophages known as Kupffer cells and play critical roles in the suppression of liver metastasis by enhancing the cells’ phagocytotic activity against cancer cells. Our study sheds light on the protective role of Kupffer cells in liver metastasis with therapeutic implications. Tumor metastasis is the cause of most cancer deaths. Although metastases can form in multiple end organs, the liver is recognized as a highly permissive organ. Nevertheless, there is evidence for immune cell-mediated mechanisms that function to suppress liver metastasis by certain tumors, although the underlying mechanisms for the suppression of metastasis remain elusive. Here, we show that Dectin-2, a C-type lectin receptor (CLR) family of innate receptors, is critical for the suppression of liver metastasis of cancer cells. We provide evidence that Dectin-2 functions in resident macrophages in the liver, known as Kupffer cells, to mediate the uptake and clearance of cancer cells. Interestingly, Kupffer cells are selectively endowed with Dectin-2–dependent phagocytotic activity, with neither bone marrow-derived macrophages nor alveolar macrophages showing this potential. Concordantly, subcutaneous primary tumor growth and lung metastasis are not affected by the absence of Dectin-2. In addition, macrophage C-type lectin, a CLR known to be complex with Dectin-2, also contributes to the suppression of liver metastasis. Collectively, these results highlight the hitherto poorly understood mechanism of Kupffer cell-mediated control of metastasis that is mediated by the CLR innate receptor family, with implications for the development of anticancer therapy targeting CLRs.

Coherent Bremsstrahlung from Si Single Crystal : I. Experiment

The interference effects in the production of bremsstrahlung in a silicon single crystal have been studied by using 720 MeV electrons. The energy spectrum of the bremsstrahlung has exhibited interference maxima of the first five orders. The intensity variation of the 150 MeV photons with the rotation of the crystal has shown also three interference Maxima on each side of the central minimum. The observed interference conditions for the photon energy and angles of incidence of electrons relative to crystal axes are in good agreement with the theory.

Growth and characterization of homogeneous YBa2Cu3O7-δ powders prepared by a freeze-drying method

Homogeneous superconducting powders of YBa2Cu3O7-δ have been successfully prepared from a carbonate solution by means of a freeze-drying method. Sintered powders at 930°C were characterized by 100% volume fraction of the superconducting phase in measurements of field-cooled magnetization at 4.5 K in low fields (\lesssim2 Oe) using a SQUID magnetometer. It turned out that large plate-shaped grains (~2×5×20 µm3) grew when the powders were heated in a short period (\gtrsim6 hours) and that the packing density was considerably high even without any pressing process.

The Production Asymmetry in γ+n→π-+p Process with Polarized Photons

The production asymmetry in the reaction γ+ n →π - + p is measured at 90° in the center-of-mass system and at five photon energies from 357 to 555 MeV. Linearly polarized photons are obtained by means of the coherent breamsstrahlung process from a silicon single crystal. Negative pions and recoiling protons from a liquid-deuterium target are detected simultaneously so that events originated from neutrons almost at rest in the deuterons are selected. The asymmetry data are compared with the dispersion-relation calculation of Berends, Donnachie, and Weaver, and with that of Schmidt et al. It is shown that the contribution from the Roper P 11 (1470) resonance is small in the pion photoproduction process.

IL‐17A‐producing CD30+ Vδ1 T cells drive inflammation‐induced cancer progression

Although it has been suspected that inflammation is associated with increased tumor metastasis, the exact type of immune response required to initiate cancer progression and metastasis remains unknown. In this study, by using an in vivo tumor progression model in which low tumorigenic cancer cells acquire malignant metastatic phenotype after exposure to inflammation, we found that IL‐17A is a critical cue for escalating cancer cell malignancy. We further demonstrated that the length of exposure to an inflammatory microenvironment could be associated with acquiring greater tumorigenicity and that IL‐17A was critical for amplifying such local inflammation, as observed in the production of IL‐1β and neutrophil infiltration following the cross‐talk between cancer and host stromal cells. We further determined that γδT cells expressing Vδ1 semi‐invariant TCR initiate cancer‐promoting inflammation by producing IL‐17A in an MyD88/IL‐23‐dependent manner. Finally, we identified CD30 as a key molecule in the inflammatory function of Vδ1T cells and the blockade of this pathway targeted this cancer immune‐escalation process. Collectively, these results reveal the importance of IL‐17A‐producing CD30+ Vδ1T cells in triggering inflammation and orchestrating a microenvironment leading to cancer progression.

Superconducting YBa2Cu3O7-δ particles prepared from freeze-dried nitrates

Homogeneous Y-Ba-Cu nitrate powders have been successfully fabricated by a freeze-drying method. Thermal decomposition of them resulted in fine superconducting YBa2Cu3O7-δ powders which were characterized by thermal analysis, SEM observation, X-ray diffraction and dc-magnetization. Results show that a rapid heating of the nitrate powders is required to obtain superconducting material of a good quality without segregation during their transitional liquid phases. In the process used, spherical YBa2Cu3O7-δ with diameters of 20-30 µm can be obtained. These results are compared to results in the case of carbonate.