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  • 1
    In: EMBO Journal, 01 August 2018, Vol.37(15), pp.n/a-n/a
    Description: Polycystic kidney disease () and other renal ciliopathies are characterized by cysts, inflammation, and fibrosis. Cilia function as signaling centers, but a molecular link to inflammation in the kidney has not been established. Here, we show that cilia in renal epithelia activate chemokine signaling to recruit inflammatory cells. We identify a complex of the ciliary kinase 1 and several ciliopathy‐related proteins including 1 and 1. At homeostasis, this ciliary module suppresses expression of the chemokine 2 in tubular epithelial cells. Deletion of 1 or 1 in mouse renal tubules elevates 2 expression in a cell‐autonomous manner and results in peritubular accumulation of 2 mononuclear phagocytes, promoting a ciliopathy phenotype. Our findings establish an epithelial organelle, the cilium, as a gatekeeper of tissue immune cell numbers. This represents an unexpected disease mechanism for renal ciliopathies and establishes a new model for how epithelial cells regulate immune cells to affect tissue homeostasis. The cilium instructs immune cell behaviour and tissue homeostasis via a complex of ciliopathy‐related proteins and the kinase 1 that together regulate chemokine signalling. Dysregulation of this system presents an unexpected disease mechanism for ciliopathies. The primary cilium transmits a signal that activates expression of chemokine CCL2. This signal is regulated through an intra‐ciliary complex of LKB1, NPHP1, polycystin 1 (PC1), ANKS3 and NEK7. Loss of LKB1 or PC1 increases CCL2 expression and peritubular macrophage numbers and promotes ciliopathy phenotypes. The Polycystic Kidney Disase (PKD) phenotype seen upon PKD1 depletion is ameliorated in the absence of cilia or tubular CCL2. A kidney‐specific inactivation of metabolic sensor 1 complex reveals a functional crosstalk between primary cilia signaling and aberrant immune cell activation .
    Keywords: Cilia ; Macrophages ; Nephronophthisis ; Polycystic Kidney Disease
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 2
    Language: English
    In: Science translational medicine, 15 January 2014, Vol.6(219), pp.219ra7
    Description: Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3-mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate-induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.
    Keywords: Microspheres ; Inflammation -- Immunology ; Monocytes -- Immunology
    ISSN: 19466234
    E-ISSN: 1946-6242
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