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Apoptosis inhibitor of macrophage (AIM) modulates the signaling in inflammatory responses, including infection, cancer, or other immune diseases. Recent studies suggest that like interleukin-10 (IL-10), AIM is involved in alternatively activated (M2) macrophage polarization. We aimed to understand whether and how AIM is involved in IL-10-induced inhibition of inflammasome activation and resolution of inflammation. First, we demonstrated that IL-10 induced increases in mRNA and protein expression of AIM in murine bone marrow-derived macrophages (BMDM). In addition, genetic and pharmacologic inhibition of STAT3 (signal transducer and activator of transcription 3) reduced IL-10-induced AIM expression. We also found that IL-10-induced STAT3 activity enhanced the AIM promoter activity by directly binding the promoter of the AIM gene. Additionally, reduction of LPS/adenosine triphosphate (ATP)-induced IL-1β production and caspase-1 activation by IL-10 was reversed in BMDM from AIM −/− mice. Treatment of BMDM from both wild type (WT) and IL-10 −/− mice with recombinant AIM showed the inhibitory effects on IL-1β and IL-18 production and caspase-1 activation. Endogenous and exogenous AIM inhibited apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) speck formation. In LPS-induced acute peritonitis, inhibition of IL-1β and IL-18 production in peritoneal lavage fluid (PLF) and serum, reduction of caspase-1 activation in peritoneal macrophages, and reduction of numbers of neutrophils and peritoneal macrophages in PLF by administration of IL-10 were not evident in AIM −/− mice. Our in vitro and in vivo data reveal a novel role of AIM in the inhibition of inflammasome-mediated caspase-1 activation and IL-1β and IL-18 production.

Growth arrest-specific 6 (Gas6) protein signaling plays a critical role in maintaining immune homeostasis and regulating inflammation. However, novel mechanisms for modulating macrophage activity through the Gas6 axis are being identified. Gas6 enhances the production of apoptosis inhibitor of macrophages (AIM), a protein with potent anti-inflammatory properties. This study investigates whether Gas6-induced AIM suppresses acute lung injury (ALI) in mice by modulating key inflammatory pathways, including inflammasome activation, autophagy, reactive oxygen species (ROS) generation, and efferocytosis. ALI was induced in wild-type (WT) and mice via intratracheal administration of LPS. To evaluate the effects of the Gas6-AIM axis on lung inflammation, recombinant Gas6 (rGas6) was treated intraperitoneally. Inflammatory responses were evaluated using enzyme-linked immunosorbent assay, a cell-sizing analyzer, and Bicinchoninic acid assays. Lung pathology was assessed using hematoxylin-eosin staining. NLRP3 inflammasome activation and autophagy were evaluated using western blot, quantitative real-time PCR, and immunofluorescence. Reactive oxygen species (ROS) levels in alveolar macrophages were measured via fluorescence microscopy, while efferocytosis was assessed in cytospin-stained BAL cells and cultured alveolar macrophages co-cultured with apoptotic Jurkat cells. Additionally, rGas6-mediated effects on NLRP3 inflammasome activation and autophagy were validated in mouse bone marrow-derived macrophages (BMDMs) using siRNAs targeting AIM, Axl, LXRα, or LXRβ. Proinflammatory cytokine production, neutrophil infiltration, and protein levels in BALF were significantly reduced by rGas6 administration in WT mice but not in mice. Specifically, rGas6 reduced IL-1β and IL-18 levels, caspase-1 activity, and the production of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) in alveolar macrophages. Additionally, rGas6 promoted autophagy and efferocytosis in alveolar macrophages while reducing ROS levels through AIM production. These protective effects were absent in mice. Furthermore, siRNA-mediated silencing of Axl, LXRα, LXRβ, or AIM reversed the inhibitory effects of rGas6 on NLRP3 inflammasome activation in BMDMs, and AIM was essential for rGas6-induced autophagy. Gas6-induced AIM production protects against LPS-induced ALI by inhibiting NLRP3 inflammasome activation, enhancing autophagy and efferocytosis, and reducing oxidative stress. These findings highlight the Gas6-AIM axis as a potential therapeutic target for mitigating inflammatory lung diseases.

Background Cell death within the tumor microenvironment (TME) plays a crucial role in controlling cancer by influencing the balance of tumor-specific immunity. Cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression through paracrine mechanisms. We found that reprogramming of CAFs by apoptotic cancer cells suppresses tumor volume and lung metastasis. Here, we investigated the mechanisms by which the interaction between apoptotic lung cancer cells and CAFs hinders tumor growth. Methods Experimental methods including CCK assay, colony formation assay, immunoblotting, co-immunoprecipitation, qRT-PCR analysis, qRT-PCR array, apoptosis assay, ELISA, and immunofluorescent staining were used in this study. Additionally, CAFs were isolated from lung tumors of Kras-mutant ( Kras LA1) mice and human lung adenocarcinoma samples using magnetic-activated cell sorting. Murine lung cancer cells (344SQ cells) along with various human cancer cell lines (A549, HCT116, and LoVo) were cultured. In animal study, conditioned medium (CM) derived from CAFs (undiluted or 50% diluted) with or without neutralizing anti-WISP-1 antibody was administered into syngeneic mice to study anti-tumoral effects. To confirm the paracrine role of WISP-1, recombinant WISP-1 (rWISP-1) was administered via intratumoral injection. Results We demonstrate that treatment with CM from lung CAFs exposed to apoptotic cancer cells suppresses proliferation and promotes apoptosis in lung cancer cells through STAT1 signaling. Pharmacologic inhibition of Notch1 activation or siRNA-mediated Notch1 silencing in CAFs reversed the antiproliferative and proapoptotic effects. Similarly, knockdown of Wnt-induced signaling protein 1 (WISP-1) in CAFs or neutralizing the CM with anti-WISP-1 antibodies reversed the antiproliferative and proapoptotic effects. WISP-1 signaled through integrin ανβ3-STAT1 signaling pathway to inhibit cancer cell growth and promote apoptosis. The in vivo introduction of CM derived from apoptotic 344SQ-exposed CAFs (ApoSQ-CAF CM) potently decelerated tumor growth. This effect was observed alongside the downregulation of proliferative and anti-apoptotic markers, while simultaneously boosting the activation of phosphorylated STAT1 and pro-apoptotic markers in CD326 + tumor cells within syngeneic immunocompetent mice. rWISP-1 effectively replicates the in vivo effects of ApoSQ-CAF CM. Conclusions These findings suggest that CM from apoptotic cancer cell-exposed CAFs may offer a promising therapeutic approach by lung cancer suppression.

Previously, we demonstrated that growth arrest-specific protein 6 (Gas6)/Axl or Mer signaling inhibited the transforming growth factor (TGF)-β1-induced epithelial–mesenchymal transition (EMT) in lung epithelial cells. Hepatocyte growth factor (HGF) has also been shown to inhibit TGF-β1-induced changes in EMT markers. Here, we examined whether Gas6 signaling can induce the production of HGF and c-Met in lung alveolar epithelial cells to mediate the inhibition of EMT and to inhibit the migration and invasion of epithelial cells. The inhibition of the RhoA/Rho kinase pathway, using either a RhoA-targeted small interfering RNA (siRNA) or the Rho kinase pharmacologic inhibitor Y27362, prevented the inhibition of TGF-β1-induced EMT in LA-4 cells and primary alveolar type II (AT II) epithelial cells. The c-Met antagonist PHA-665752 also blocked the anti-EMT effects associated with Gas6. Moreover, treatment with Y27362 or PHA-665752 prevented the Gas6-mediated inhibition of TGF-β1-induced migration and invasion. Our data provided evidence that the RhoA-dependent production of HGF and c-Met mediated the Gas6-induced inhibition of EMT, migration and invasion in lung alveolar epithelial cells. Thus, Gas6/Axl and Mer/RhoA signaling may be necessary for the maintenance of homeostasis in the alveolar epithelium, via HGF and c-Met.

The interplay between apoptotic cancer cells and the tumor microenvironment modulates cancer progression and metastasis. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting these events through paracrine communication. Here, we demonstrate that conditioned medium (CM) from lung CAFs exposed to apoptotic cancer cells suppresses TGF-β1-induced migration and invasion of cancer cells and CAFs. Direct exposure of CAFs to apoptotic 344SQ cells (ApoSQ) inhibited CAF migration and invasion and the expression of CAF activation markers. Enhanced secretion of Wnt‐induced signaling protein 1 (WISP-1) by CAFs exposed to ApoSQ was required for these antimigratory and anti-invasive effects. Pharmacological inhibition of Notch1 activation or siRNA-mediated Notch1 silencing prevented WISP-1 production by CAFs and reversed the antimigratory and anti-invasive effects. Enhanced expression of the Notch ligand delta-like protein 1 on the surface of ultraviolet-irradiated apoptotic lung cancer cells triggered Notch1-WISP-1 signaling. Phosphatidylserine receptor brain-specific angiogenesis inhibitor 1 (BAI1)-Rac1 signaling, which facilitated efferocytosis by CAFs, participated in crosstalk with Notch1 signaling for optimal production of WISP-1. In addition, a single injection of ApoSQ enhanced WISP-1 production, suppressed the expression of CAF activation markers in isolated Thy1+ CAFs, and inhibited lung metastasis in syngeneic immunocompetent mice via Notch1 signaling. Treatment with CM from CAFs exposed to ApoSQ suppressed tumor growth and lung metastasis, whereas treatment with WISP-1-immunodepleted CM from CAFs exposed to ApoSQ reversed the antitumorigenic and antimetastatic effects. Therefore, treatment with CM from CAFs exposed to apoptotic lung cancer cells could be therapeutically applied to suppress CAF activation, thereby preventing cancer progression and metastasis.

Cell death within the tumor microenvironment (TME) plays a pivotal role in shaping tumor-specific immunity. The dynamic interplay between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) is central to tumor progression and immune regulation. Here, we show that conditioned medium (CM) from lung CAFs exposed to apoptotic cancer cells selectively impairs the survival of M2-like macrophages, induces apoptosis, and promotes their reprogramming toward an M1-like phenotype. These effects were abrogated by knockdown of Wnt-induced signaling protein 1 (WISP-1) in CAFs, identifying WISP-1 as a key paracrine effector. Mechanistically, WISP-1 signals through the integrin α5β3-STAT1 axis to mediate M2 TAM apoptosis and M1-like reprogramming. , intratumoral injection of CM derived from CAF exposed to apoptotic 344SQ cells reduced overall TAM density, decreased the proportion of M2-like TAMs, and promoted their reprogramming toward an M1-like phenotype, accompanied by STAT1 activation in M2 TAMs. This phenotypic shift was associated with increased infiltration of cytotoxic CD8 T cells and reduced accumulation of regulatory T cells within the tumor. Notably, these effects were abolished by either depletion of WISP-1 from the CM or pharmacological inhibition of STAT1 following recombinant WISP-1 administration. Collectively, our findings identify the WISP-1-integrin α5β3-STAT1 axis as a novel therapeutic target for TAM reprogramming and tumor suppression in lung cancer.

Cell death within the tumor microenvironment (TME) plays a crucial role in controlling cancer by influencing the balance of tumor-specific immunity. Cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression through paracrine mechanisms. We found that reprogramming of CAFs by apoptotic cancer cells suppresses tumor volume and lung metastasis. Here, we investigated the mechanisms by which the interaction between apoptotic lung cancer cells and CAFs hinders tumor growth. Experimental methods including CCK assay, colony formation assay, immunoblotting, co-immunoprecipitation, qRT-PCR analysis, qRT-PCR array, apoptosis assay, ELISA, and immunofluorescent staining were used in this study. Additionally, CAFs were isolated from lung tumors of Kras-mutant (KrasLA1) mice and human lung adenocarcinoma samples using magnetic-activated cell sorting. Murine lung cancer cells (344SQ cells) along with various human cancer cell lines (A549, HCT116, and LoVo) were cultured. In animal study, conditioned medium (CM) derived from CAFs (undiluted or 50% diluted) with or without neutralizing anti-WISP-1 antibody was administered into syngeneic mice to study anti-tumoral effects. To confirm the paracrine role of WISP-1, recombinant WISP-1 (rWISP-1) was administered via intratumoral injection. We demonstrate that treatment with CM from lung CAFs exposed to apoptotic cancer cells suppresses proliferation and promotes apoptosis in lung cancer cells through STAT1 signaling. Pharmacologic inhibition of Notch1 activation or siRNA-mediated Notch1 silencing in CAFs reversed the antiproliferative and proapoptotic effects. Similarly, knockdown of Wnt-induced signaling protein 1 (WISP-1) in CAFs or neutralizing the CM with anti-WISP-1 antibodies reversed the antiproliferative and proapoptotic effects. WISP-1 signaled through integrin [alpha]ν[beta]3-STAT1 signaling pathway to inhibit cancer cell growth and promote apoptosis. The in vivo introduction of CM derived from apoptotic 344SQ-exposed CAFs (ApoSQ-CAF CM) potently decelerated tumor growth. This effect was observed alongside the downregulation of proliferative and anti-apoptotic markers, while simultaneously boosting the activation of phosphorylated STAT1 and pro-apoptotic markers in CD326.sup.+ tumor cells within syngeneic immunocompetent mice. rWISP-1 effectively replicates the in vivo effects of ApoSQ-CAF CM. These findings suggest that CM from apoptotic cancer cell-exposed CAFs may offer a promising therapeutic approach by lung cancer suppression.

Superradiance is a quantum phenomenon that occurs when emitters are sufficiently close to change spontaneous emission. Controlling the position and state of emitters within an atomic ensemble, however, is technically challenging. Kim et al. show that spatial correlations can be replaced by temporal correlations to achieve superradiance (see the Perspective by Meschede). They dropped prepared atoms into a high-quality optical cavity and found that the number of photons within the cavity built up superradiantly as the atoms dropped through one by one. The method provides a versatile platform for generating nonclassical states of light. Science , this issue p. 662 ; see also p. 641 Atoms dropped through an optical cavity produce an enhanced emission of photons. Superradiance is a quantum phenomenon emerging in macroscopic systems whereby correlated single atoms cooperatively emit photons. Demonstration of controlled collective atom-field interactions has resulted from the ability to directly imprint correlations with an atomic ensemble. Here we report cavity-mediated coherent single-atom superradiance: Single atoms with predefined correlation traverse a high–quality factor cavity one by one, emitting photons cooperatively with the N atoms that have already gone through the cavity ( N represents the number of atoms). Enhanced collective photoemission of N -squared dependence was observed even when the intracavity atom number was less than unity. The correlation among single atoms was achieved by nanometer-precision position control and phase-aligned state manipulation of atoms by using a nanohole-array aperture. Our results demonstrate a platform for phase-controlled atom-field interactions.

Emission and absorption of light lie at the heart of light–matter interaction1. Although emission and absorption rates are regarded as intrinsic properties of atoms and molecules, various ways to modify these rates have been sought in applications such as quantum information processing2, metrology3 and light-energy harvesting4. One promising approach is to utilize collective behaviour of emitters in the same way as in superradiance5. Although superradiance has been observed in diverse systems3,6–10, its conceptual counterpart in absorption has never been realized11 until now. Here we demonstrate enhanced cooperative absorption—superabsorption—by implementing a time-reversal process of superradiance. The observed superabsorption rate is much higher than that of ordinary absorption, with the number of absorbed photons scaling with the square of the number of atoms, exhibiting the cooperative nature of superabsorption. The present superabsorption—which performs beyond the limitations of conventional absorption—can facilitate weak-signal sensing1, light-energy harvesting11 and light–matter quantum interfaces2.The counterpart of superradiance, called superabsorption, has now been observed. Superabsorption rates are much higher than that of ordinary absorption and may enable weak-signal exploitation.

Performance of nano- and microscale heat engines can be improved with the help of quantum-mechanical phenomena. Recently, heat reservoirs with quantum coherence have been proposed to enhance engine performance beyond the Carnot limit even with a single reservoir. However, no physical realizations have been achieved so far. Here we report the first proof-of-principle experimental demonstration of a photonic quantum engine driven by superradiance employing a single heat reservoir composed of atoms and photonic vacuum. Reservoir atoms prepared in a quantum coherent superposition state underwent superradiance as they traversed the cavity. This led to about 40-fold increase in the effective engine temperature, resulting in near-unity engine efficiency. Moreover, the observed engine output power grew quadratically with respect to the atomic injection rate. Our work can be utilized in quantum-mechanical heat transfer as well as in boosting engine powers, opening a pathway to the development of photomechanical devices that run on quantum coherence embedded in heat baths.A superradiant photonic engine is developed by using a 138Ba atomic beam and a high-finesse optical cavity. The mirrors of a Fabry–Pérot cavity act as the piston of an engine. The achieved engine temperature and efficiency are 1.5 × 105 K and 98%, respectively.