Biology subjects

Nozaki, K.

Publications and source records attributed to Nozaki, K..

3 recordsLinked to original sources

bioRxiv2026

Extrinsic MMPs drive epithelial shape change via basal ECM disassembly in the Drosophila wing disc

Epithelial morphogenesis generates complex tissue architectures with remarkable reproducibility, yet how such self-organized shape transformations are triggered in vivo remains poorly understood. Here, we show that epithelial morphogenesis during early pupal development of the Drosophila wing disc is regulated non-autonomously through remodeling of the basal extracellular matrix (ECM) by neighboring tissues. Live imaging analyses reveal a previously unrecognized epithelial shape transition at the larval-to-pupal stage, in which the wing disc epithelium transforms from a concave to a convex configuration. Rather than being driven autonomously by the epithelium, this morphogenetic transition depends on adjacent non-epithelial cell populations, including myoblasts and tracheal cells. Mechanistically, systemic ecdysone signaling activates Mmp1 and Mmp2 in these neighboring tissues, leading to spatially restricted basal ECM disassembly that permits collective epithelial shape reorganization. Together, our findings establish ECM remodeling at tissue interfaces as a non-autonomous regulatory layer that enables epithelial self-organization during development.

developmental biology↗

bioRxiv2024

NLRP3, NLRP6, and NLRP12 are inflammasomes with distinct expression patterns

Inflammasomes are sensors that detect cytosolic microbial molecules or cellular damage, and in response they initiate a form of lytic regulated cell death called pyroptosis. Inflammasomes signal via homotypic protein-protein interactions where CARD or PYD domains are crucial for recruiting downstream partners. Here, we screened these domains from NLR family proteins, and found that the PYD domain of NLRP6 and NLRP12 could activate caspase-1 to induce cleavage of IL-1{beta} and GSDMD. Inflammasome reconstitution verified that full length NLRP6 and NLRP12 formed inflammasomes in vitro, and NLRP6 was more prone to auto-activation. NLRP6 was highly expressed in intestinal epithelial cells (IEC), but not in immune cells. Molecular phylogeny analysis found that NLRP12 was closely related to NLRP3, but the activation mechanisms are different. NLRP3 was highly expressed in monocytes and macrophages, and was modestly but appreciably expressed in neutrophils. In contrast, NLRP12 was specifically expressed in neutrophils and eosinophils, but was not detectable in macrophages. NLRP12 mutations cause a periodic fever syndrome called NLRP12 autoinflammatory disease. We found that several of these patient mutations caused spontaneous activation of caspase-1 in vitro, which likely causes their autoinflammatory disease. Different cell types have unique cellular physiology and structures which could be perturbed by a pathogen, necessitating expression of distinct inflammasome sensors to monitor for signs of infection.

immunology↗

bioRxiv2021

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

Inflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1{beta} and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1{beta} expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation. SIGNIFICANCE STATEMENTInflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1{beta}, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1{beta}-mediated inflammation.

immunology↗