Allergin-1 on mast cells suppresses house dust mite-induced airway hyperresponsiveness in mice

Although airway hyperresponsiveness (AHR) is a prominent feature of asthma, how it is regulated remains incompletely understood. Allergin-1, an inhibitory immunoglobulin-like receptor containing an immunoreceptor tyrosine-based inhibitory motif (ITIM), is expressed on human and mouse mast cells (MCs) and inhibits high-affinity receptor for IgE (FcεRI)-mediated signaling. Using MC-deficient KitW-sh/W-sh mice and Mas-TRECK mice, which carries a diphtheria toxin (DT)-induced MC deletion system based on il4 enhancer elements, we demonstrate here that MCs are involved in the induction of house dust mite (HDM)-induced AHR. Further, we show that MCs deficient in Allergin-1 exacerbated HDM-induced AHR, but had no effect on airway inflammation. In vitro analysis demonstrated that Allergin-1 inhibited anti-HDM allergen antibody-dependent HDM allergen-mediated degranulation by MCs. Thus, Allergin-1 on MCs plays an important role in the regulation of HDM-induced AHR

Differential isoform expression of Allergin-1 during acute and chronic inflammation

Introduction: Neutrophils are crucial to antimicrobial defense, but excessive neutrophilic inflammation elicits immune pathology. Currently, no effective treatment exists to curb neutrophil activation. However, neutrophils express a variety of inhibitory receptors which may represent potential therapeutic targets to limit neutrophilic inflammation. Indeed, we previously showed that the inhibitory collagen receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) regulates neutrophilic airway inflammation and inhibits neutrophil extracellular trap formation. The inhibitory receptor Allergin-1 is expressed by myeloid cells and B cells. Allergin-1 suppresses mast cell and basophil activation, but a potential regulatory role on neutrophils remains unexplored. We aimed to demonstrate the regulation of neutrophils by Allergin-1. Methods: We examine Allergin-1 isoform expression on human neutrophils during homeostatic (healthy donors) and chronic inflammatory (systemic lupus erythematosus patients) conditions in comparison to other circulating leukocytes by flow cytometry. To reveal a potential role for Allergin-1 in regulating neutrophilic inflammation, we experimentally infect wild-type (WT) and Allergin-1-deficient mice with a respiratory syncytial virus (RSV) and monitor disease severity and examine cellular airway infiltrate. Flow cytometry was used to confirm Allergin-1 expression by airway-infiltrated neutrophils in RSV infection-induced bronchiolitis patients. Results: Only the short 1 (S1) isoform, but not the long (L) or S2 isoform could be detected on blood leukocytes, with the exception of nonclassical monocytes, which exclusively express the S2 isoform. Allergin-1 expression levels did not vary significantly between healthy individuals and patients with the systemic inflammatory disease on any interrogated cell type. Airway-infiltrated neutrophils of pediatric RSV bronchiolitis patients were found to express Allergin-1S1. However, Allergin-1-deficient mice experimentally infected with RSV did not show exacerbated disease or increased neutrophil airway infiltration compared to WT littermates. Conclusion: Allergin-1 isoform expression is unaffected by chronic inflammatory conditions. In stark contrast to fellow inhibitory receptor LAIR-1, Allergin-1 does not regulate neutrophilic inflammation in a mouse model of RSV bronchiolitis

Allergin-1 inhibits TLR2-mediated mast cell activation and suppresses dermatitis

TLR2 recognizes cell wall components of Staphylococcus aureus, which colonizes >90% of atopic eczematous skin lesions. The regulatory mechanisms of TLR2 signaling in the skin remain unclear. Allergin-1, an inhibitory immunoglobulin-like receptor containing an ITIM, is expressed on mast cells (MCs) and inhibits IgE-mediated anaphylaxis in mice. Here, we show that Allergin-1 inhibits TLR2-mediated activation of, and inflammatory cytokine production by, MCs in vitro. Compared with wild-type mice, Allergin-1-deficient mice showed enhanced ear swelling with enhanced collagen deposition and greater Ly6G+ neutrophil recruitment after intra-dermal injection of Pam2CSK4 into pinnae. Using Mas–TRECK mice, which is an MC deletion system based on il4 enhancer elements, we also demonstrated that Allergin-1 on MCs is responsible for the Pam2CSK4-induced ear swelling. These results suggest that Allergin-1 on skin MCs suppresses TLR2-induced dermatitis

Comparative study of stress and strain partitioning behaviors in medium manganese and transformation-induced plasticity-aided bainitic ferrite steels

引張強度と伸びが同程度のM-Mn鋼とTBF鋼の優れた加工硬化性の起源を放射光を利用したX線回折法によって比較検討した。M-Mn鋼はオーステナイトで優先的に塑性変形し、その優れた加工硬化能とそれに伴う均一な伸びは、保持されたオーステナイトのマルテンサイト変態と転位蓄積の割合が高いことに起因する。一方、TBF鋼の優れた加工硬化挙動と均一な伸びは、オーステナイト相の高い安定性とオーステナイトのすべり変形に対する高い抵抗性により、大きなひずみが発生するまで変態性が持続し、FCCとBCC間で大きな応力分配が行われることに起因する

Effects of stress and plastic strain on hydrogen embrittlement fracture of a U-bent martensitic steel sheet

U曲げマルテンサイト鋼板試験片の水素脆化破壊におよぼす応力と塑性ひずみ分布の影響を調査した。U曲げ試験片の水素脆化試験を実施した。水素を帯びたU曲げ試験片の内部に、主に粒界破壊からなる破壊形態が見られ、内部で亀裂発生およびU曲げ鋼板の両面付近にシャリップが見られた。シンクロトロンX線回折測定と有限要素シミュレーションを利用して、U曲げ試験片の厚さ方向の応力と塑性ひずみの分布を分析した。測定により得られた弾性ひずみ分布は、シミュレーションとよく一致していた。水素を充填したU曲げ試験片の亀裂発生部位は、引張応力が最も高い領域に対応していると考えられ、最大引張応力が主に亀裂発生を決定することを示唆していた

Potent Anti-R5 Human Immunodeficiency Virus Type 1 Effects of a CCR5 Antagonist, AK602/ONO4128/GW873140, in a Novel Human Peripheral Blood Mononuclear Cell Nonobese Diabetic-SCID, Interleukin-2 Receptor γ-Chain-Knocked-Out AIDS Mouse Model

We established human peripheral blood mononuclear cell (PBMC)-transplanted R5 human immunodeficiency virus type 1 isolate JR-FL (HIV-1(JR-FL))-infected, nonobese diabetic-SCID, interleukin 2 receptor γ-chain-knocked-out (NOG) mice, in which massive and systemic HIV-1 infection occurred. The susceptibility of the implanted PBMC to the infectivity and cytopathic effect of R5 HIV-1 appeared to stem from hyperactivation of the PBMC, which rapidly proliferated and expressed high levels of CCR5. When a novel spirodiketopiperazine-containing CCR5 inhibitor, AK602/ONO4128/GW873140 (molecular weight, 614), was administered to the NOG mice 1 day after R5 HIV-1 inoculation, the replication and cytopathic effects of R5 HIV-1 were significantly suppressed. In saline-treated mice (n = 7), the mean human CD4(+)/CD8(+) cell ratio was 0.1 on day 16 after inoculation, while levels in mice (n = 8) administered AK602 had a mean value of 0.92, comparable to levels in uninfected mice (n = 7). The mean number of HIV-RNA copies in plasma in saline-treated mice were ∼10(6)/ml on day 16, while levels in AK602-treated mice were 1.27 × 10(3)/ml (P = 0.001). AK602 also significantly suppressed the number of proviral DNA copies and serum p24 levels (P = 0.001). These data suggest that the present NOG mouse system should serve as a small-animal AIDS model and warrant that AK602 be further developed as a potential therapeutic for HIV-1 infection