Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors

Schledzewski, Kai; Géraud, Cyrill; Arnold, Bernd; Wang, Shijun; Gröne, Hermann Josef; Kempf, Tibor; Wollert, Kai C.; Straub, Beate K.; Schirmacher, Peter; Demory, Alexandra; Schönhaber, Hiltrud; Gratchev, Alexei; Dietz, Lisa; Thierse, Hermann‐Josef; Kzhyshkowska, Julia; Goerdt, Sergij

doi:10.1172/jci44740

Cited by 140 publications

(182 citation statements)

References 58 publications

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“…Proteomic analysis of baseline serum samples demonstrated increased levels of several proteins in the serum of stabilin-1 −/− mice compared with WT mice (SI Appendix, Table S1), several of which are related to oxidative stress. However, we did not detect increased circulatory levels of proinflammatory or profibrogenic cytokines such as TGF-β and PDGF A and B, in keeping with previous studies (13).…”

Section: Stabilin-1 Deficiency Leads To a Reduction Of Ceroid Macrophsupporting

confidence: 92%

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Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Rantakari

Patten

Valtonen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

108

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Macrophages are key regulators of fibrosis development and resolution. Elucidating the mechanisms by which they mediate this process is crucial for establishing their therapeutic potential. Here, we use experimental models of liver fibrosis to show that deficiency of the scavenger receptor, stabilin-1, exacerbates fibrosis and delays resolution during the recovery phase. We detected a subset of stabilin-1 + macrophages that were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL (MDA-LDL) uptake by hepatic macrophages and was associated with excess collagen III deposition. Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the profibrogenic chemokine CCL3 and an increase in GFAP + fibrogenic cells. Stabilin-1 −/− macrophages demonstrated a proinflammatory phenotype during liver injury and the normal induction of Ly6C lo monocytes during resolution was absent in stabilin-1 knockouts leading to persistence of fibrosis. Human stabilin-1 + monocytes efficiently internalized MDA-LDL and this suppressed their ability to secrete CCL3, suggesting that loss of stabilin-1 removes a brake to CCL3 secretion. Experiments with cell-lineage-specific knockouts revealed that stabilin-1 expression in myeloid cells is required for the induction of this subset of macrophages and that increased fibrosis occurs in their absence. This study demonstrates a previously unidentified regulatory pathway in fibrogenesis in which a macrophage scavenger receptor protects against organ fibrosis by removing fibrogenic products of lipid peroxidation. Thus, stabilin-1 + macrophages shape the tissue microenvironment during liver injury and healing.stabilin-1 | liver | fibrosis | macrophages | CCL3

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Section: Stabilin-1 Deficiency Leads To a Reduction Of Ceroid Macrophsupporting

confidence: 92%

“…1 A and B) (13). Following CCl 4 administration, stabilin-1 −/− mice developed a marked increase in hepatic scar formation compared with WT mice with features of bridging fibrosis ( Fig.…”

Section: Significancementioning

confidence: 91%

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Rantakari

Patten

Valtonen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

108

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“…HSECs and Kupffer cells express various types of scavenger receptors to fulfill the filter functions. Among those scavenger receptors, Stabilin-1 (Stab1, also known as FEEL-1 and CLEVER-1) and Stabilin-2 (Stab2, also known as FEEL-2 and HARE) are structurally related, exhibiting 55% homology at the protein level, and expressed on HSECs (2).…”

mentioning

confidence: 99%

“…Despite these two glycoproteins' structural similarity, the spectrum of their ligands differs significantly. Stab1 is expressed on lymphatic vessels and macrophages as well as HSEC and binds to acetylated lowdensity lipoprotein (ac-LDL), secreted protein acidic and rich in cysteine, placental lactogen, growth differentiation factor 15, and Gram-positive and Gram-negative bacteria, but not to HA (2,(4)(5)(6)(7)(8). It also mediates leukocyte trafficking (9).…”

mentioning

confidence: 99%

“…Stab2 is expressed on the sinusoid endothelium in the liver, spleen, and lymph nodes and has been used as a specific marker for HSECs (10). It binds to and mediates the endocytosis of HA, advanced glycation end products-modified protein, and heparin in addition to ac-LDL, growth differentiation factor 15, and bacteria (2,4). Stab2 also recognizes membrane phosphatidylserine of apoptotic cells (11).…”

mentioning

confidence: 99%

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Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis

Hirose¹,

Saijou²,

Sugano³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hyaluronic acid (HA) has been implicated in the proliferation and metastasis of tumor cells. However, most previous studies were conducted on extracellular matrix or pericellular HA, and the role of circulating HA in vivo has not been studied. HA is rapidly cleared from the bloodstream. The scavenger receptor Stabilin-2 (Stab2) is considered a major clearance receptor for HA. Here we report a dramatic elevation in circulating HA levels in Stab2-deficient mice without any overt phenotype. Surprisingly, the metastasis of B16F10 melanoma cells to the lungs was markedly suppressed in the Stab2-deficient mice, whereas cell proliferation was not affected. Furthermore, administration of an anti-Stab2 antibody in Stab2 + mice elevated serum HA levels and prevented the metastasis of melanoma to the lung, and also suppressed spontaneous metastasis of mammary tumor and human breast tumor cells inoculated in the mammary gland. Administration of the antibody or high-dose HA in mice blocked the lodging of melanoma cells to the lungs. Furthermore, HA at high concentrations inhibited the rolling/tethering of B16 cells to lung endothelial cells. These results suggest that blocking Stab2 function prevents tumor metastasis by elevating circulating HA levels. Stab2 may be a potential target in antitumor therapy.cancer | hyaluronan | imaging | antibody therapy | sinusoid

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Phenotypical and biochemical characterization of murine psoriasiform and fibrotic skin disease models in Stabilin‐deficient mice

Krzistetzko,

Géraud,

Dormann

et al. 2024

FEBS Open Bio

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Stabilin‐1 (Stab1) and Stabilin‐2 (Stab2) are scavenger receptors expressed by liver sinusoidal endothelial cells (LSECs). The Stabilin‐mediated scavenging function is responsible for regulating the molecular composition of circulating blood in mammals. Stab1 and Stab2 have been shown to influence fibrosis in liver and kidneys and to modulate inflammation in atherosclerosis. In this context, circulating and localized TGFBi and POSTN are differentially controlled by the Stabilins as their receptors. To assess Stab1 and Stab2 functions in inflammatory and fibrotic skin disease, topical Imiquimod (IMQ) was used to induce psoriasis‐like skin lesions in mice and Bleomycin (BLM) was applied subcutaneously to induce scleroderma‐like effects in the skin. The topical treatment with IMQ, as expected, led to psoriasis‐like changes in the skin of mice, including increased epidermal thickness and significant weight loss. Clinical severity was reduced in Stab2‐deficient compared to Stab1‐deficient mice. We did not observe differential effects in the skin of Stabilin‐deficient mice after bleomycin injection. Interestingly, treatment with IMQ led to a significant increase of Stabilin ligand TGFBi plasma levels in Stab2−/− mice, treatment with BLM resulted in a significant decrease in TGFBi levels in Stab1−/− mice. Overall, Stab1 and Stab2 deficiency resulted in minor alterations of the disease phenotypes accompanied by alterations of circulating ligands in the blood in response to the disease models. Stabilin‐mediated clearance of TGFBi was altered in these disease processes. Taken together our results suggest that Stabilin deficiency‐associated plasma alterations may interfere with preclinical disease severity and treatment responses in patients.

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Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors

Cited by 140 publications

References 58 publications

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis

Phenotypical and biochemical characterization of murine psoriasiform and fibrotic skin disease models in Stabilin‐deficient mice

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