Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents Burkholderia thailandensis-Induced Multinucleated Giant Cell Formation

The Gram-negative bacteria of the Burkholderia species are associated with human diseases ranging from pneumonia to life-threatening melioidosis. Upon infection through inhalation, ingestion, or the percutaneous route, these bacteria can spread and establish granuloma-like lesions resulting from the fusion of host cells to form multinucleated giant cells (MNGCs). Burkholderia resistance to several antibiotics highlights the importance to better understand how the innate immune system controls infections.

Cholesterol granuloma of the maxillary sinus: a forgotten entity

Aim of the study: Cholesterol granuloma is a histological entity which consists of granulation tissue in which a large quantity of cholesterol crystals provoke foreign body giant cell formation. Cholesterol granulomas are often found in the middle ear with rare presentation in the paranasal sinus. We would like to highlight the diagnostic challenges and the management of maxillary sinus cholesterol granuloma in a young woman presenting as a unilateral nasal mass. Case study: We report a young woman with cholesterol granuloma of maxillary sinus who initially presented with unilateral nasal obstruction. Rigid nasoendoscopy and imaging were suggestive of an antrochoanal polyp. Ipsilateral functional endoscopic sinus surgery was done successfully. Conclusion: Albeit rare, cholesterol granuloma ought to be considered a differential diagnosis in a sinonasal tumour. This case report highlights the rare presentation of maxillary sinus cholesterol granuloma which ought to be considered a differential diagnosis of a unilateral nasal mass.

Nuclear localization of p65 reverses therapy induced senescence

Senescence is a tumor suppressor phenomenon. We have earlier shown that therapy induced senescence in residual disease glioblastoma (GBM) cells can reverse leading to relapse. Here we demonstrate that ciprofloxacin induced senescence in glioma-derived cell lines and primary cultures defined by β-gal positivity, SASP release, giant-cell formation, higher ROS, p-ATM, γ-H2AX, and senescence gene signature have three stages- initiation, pseudo-senescence and permanent-senescence. Drug withdrawal during initiation and pseudo-senescence reinitiated proliferation in vitro and tumor formation in vivo. Importantly, prolonged ciprofloxacin treatment induced permanent-senescence that failed to reverse following drug withdrawal. RNA-Seq revealed downregulated p65 transcription network and incremental SMAD pathway genes expression from initiation to permanent-senescence. Drug withdrawal at initiation and pseudo-senescence but not permanent-senescence increased p65 nuclear localization, and escape from senescence. In contrast, permanent-senescent cells showed loss of nuclear p65 and increased apoptosis. Pharmacological or genetic p65 knockdown upholds senescence in vitro and inhibit tumor formation in vivo. Together, this study demonstrates that levels of nuclear p65 defines the window of therapy induced senescence reversibility and coupling senotherapeutic drugs with p65 inhibitors induce permanent-senescence in GBM cells.

First person – Patricia Joyce Brooks

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Patricia Joyce Brooks is first author on ‘CD301 mediates fusion in IL-4-driven multinucleated giant cell formation’, published in JCS. Patricia conducted the research described in this article while a PhD student in Christopher A. McCulloch and Michael Glogauer's lab at the Faculty of Dentistry, University of Toronto, Canada. Patricia is now a postdoctoral research fellow in the lab of Scott Bratman at the Princess Margaret Research Institute, Toronto, Canada, where she is bringing clinical oral pathology diagnostic challenges to the benchtop to establish better testing at the basic science level.

CD301 mediates fusion in IL-4-driven multinucleated giant cell formation

ABSTRACTMultinucleated giant cells (MGCs) are prominent in foreign body granulomas, infectious and inflammatory processes, and auto-immune, neoplastic and genetic disorders, but the molecular determinants that specify the formation and function of these cells are not defined. Here, using tandem mass tag-mass spectrometry, we identified a differentially upregulated protein, C-type lectin domain family 10 member (herein denoted CD301, also known as CLEC10A), that was strongly upregulated in mouse RAW264.7 macrophages and primary murine macrophages undergoing interleukin (IL-4)-induced MGC formation. CD301+ MGCs were identified in biopsy specimens of human inflammatory lesions. Function-inhibiting CD301 antibodies or CRISPR/Cas9 deletion of the two mouse CD301 genes (Mgl1 and Mgl2) inhibited IL-4-induced binding of N-acetylgalactosamine-coated beads by 4-fold and reduced MGC formation by 2.3-fold (P<0.05). IL-4-driven fusion and MGC formation were restored by re-expression of CD301 in the knockout cells. We conclude that in monocytes, IL-4 increases CD301 expression, which mediates intercellular adhesion and fusion processes that are required for the formation of MGCs.This article has an associated First Person interview with the first author of the paper.

Multinucleated Giant Cell Formation as a Portal to Chronic Bacterial Infections

This review provides a snapshot of chronic bacterial infections through the lens of Burkholderia pseudomallei and detailing its ability to establish multi-nucleated giant cells (MNGC) within the host, potentially leading to the formation of pyogranulomatous lesions. We explore the role of MNGC in melioidosis disease progression and pathology by comparing the similarities and differences of melioidosis to tuberculosis, outline the concerted events in pathogenesis that lead to MNGC formation, discuss the factors that influence MNGC formation, and consider how they fit into clinical findings reported in chronic cases. Finally, we speculate about future models and techniques that can be used to delineate the mechanisms of MNGC formation and function.

Multinucleated Giant Cell Formation as a Portal to Chronic Bacterial Infections

This review provides a snapshot of chronic bacterial infections through the lens of Burkholderia pseudomallei; detailing its ability to establish multi-nucleated giant cells (MNGC) within the host, leading to the formation of pyogranulomatous lesions. We explore the role of MNGC in melioidosis disease progression and pathology by comparing the similarities and differences of melioidosis to tuberculosis, outlining the concerted events in pathogenesis that lead to MNGC formation, discussing the factors that influence MNGC formation and how they fit into clinical findings reported in chronic cases. Finally, we speculate about future models and techniques that can be used to delineate the mechanisms of MNGC formation and function.