Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis

Han, Ho Jae; Ge, Xiaodong; Komakula, Sai Santosh Babu; Désert, Romain; Das, Sukanta; Song, Zhuolun; Chen, Wei; Athavale, Dipti; Gaskell, Harriet; Lantvit, Daniel D.; Guzman, Grace; Nieto, Natalia

doi:10.1053/j.gastro.2023.03.228

Cited by 43 publications

(24 citation statements)

References 43 publications

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“…These observations are in line with the reported role of intracellular SPP1 as a toll-like receptor signaling modulator 48 . In addition, a recent study in experimental NASH showed that myeloid-specific Spp1 ablation aggravated liver inflammation, while myeloid-specific knock-in conferred protection, supporting our data 49 . Our data show that both Spp1 and Trem2 are upregulated in experimental PSC-associated MoMFs, but Spp1 rather than Trem2 was the most prominent differentially expressed marker when comparing MoMFs versus KCs.…”

Section: Discussionsupporting

confidence: 93%

“…Our data show a divergent role for SPP1, on the one hand intracellularly in MFs and on the other hand secreted extracellularly, which supports previous studies in this regard. [48,49,[51][52][53] Further studies elucidating the more precise origin and role of secreted SPP1 in experimental PSC, including determining the relative levels of SPP1-specific isoforms and the balance between secreted and intracellular-related events, will be of interest. The tools to study this are currently being further developed.…”

Section: Discussionmentioning

confidence: 99%

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Osteopontin characterizes bile duct–associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis

De Muynck,

Heyerick,

De Ponti

et al. 2023

Hepatology

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Background & Aims: Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which pharmacological treatment options are currently unavailable. PSC is strongly associated with colitis and a disruption of the gut-liver axis, and macrophages are involved in the pathogenesis of PSC. However, how gut-liver interactions and specific macrophage populations contribute to PSC is incompletely understood. Approach & Results: We investigated the impact of cholestasis and colitis on the hepatic and colonic microenvironment, and performed an in depth characterization of hepatic macrophage dynamics and function in models of concomitant cholangitis and colitis. Cholestasis-induced fibrosis was characterized by depletion of resident Kupffer cells, and enrichment of monocytes and monocyte-derived macrophages (MoMFs) in the liver. These MoMFs highly express triggering-receptor-expressed-on-myeloid-cells-2 (Trem2) and osteopontin (Spp1), markers assigned to hepatic bile duct associated macrophages, and were enriched around the portal triad, which was confirmed in human PSC. Colitis induced monocyte/macrophage infiltration in the gut and liver, enhanced cholestasis-induced MoMF-Trem2 and Spp1 upregulation, yet did not exacerbate liver fibrosis. Bone marrow chimeras showed that knockout of Spp1 in infiltrated MoMFs exacerbates inflammation in vivo and in vitro, while mAb-mediated neutralization of SPP1 confered protection in experimental PSC. In human PSC patients, serum osteopontin levels are elevated compared to control, and significantly increased in advanced stage PSC and might serve as prognostic biomarker for liver transplant-free survival. Conclusions: Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as prognostic marker and future therapeutic target in PSC.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Osteopontin characterizes bile duct–associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis

De Muynck,

Heyerick,

De Ponti

et al. 2023

Hepatology

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“…Along those lines, a recent study using myeloid-specific Spp1 ablation or Spp1 overexpression in experimental steatohepatitis demonstrated that Spp1 deficiency increased the inflammatory potential of myeloid cells, resulting in aggravated disease. [10] Lastly, the authors investigated the reciprocal effects of cholestatic liver disease and intestinal injury. Colitis alone induced liver inflammation, as ALT levels, broad markers of inflammation, and myeloid cells increased in the liver without any development of fibrosis.…”

mentioning

confidence: 99%

“…The role of osteopontin in liver disease has been studied extensively, yielding ambiguous results. [9] With its abundant expression, global knockouts or antibody targeting might be insufficient to understand the precise cellular and molecular mechanisms, as demonstrated by De Muynck et al [8,10] Further complicating matters, OPN comes in different isoforms with different biological functions, and global knockouts will thus have a different phenotype compared to recombinant OPN or neutralizing antibodies, which only block extracellular OPN. [9] Furthermore, LAMs might come in different flavors, displaying a higher degree of plasticity explaining some of the ambiguous published results.…”

mentioning

confidence: 99%

“…These data indicate that LAMs in aggregate provide protection, potentially by means of Spp1 or other functional molecules upstream or downstream of osteopontin, while osteopontin released by other cells, potentially the injured cholangiocytes, might have an opposing effect in aggregate propagating disease by yet unexplored mechanisms. Along those lines, a recent study using myeloid-specific Spp1 ablation or Spp1 overexpression in experimental steatohepatitis demonstrated that Spp1 deficiency increased the inflammatory potential of myeloid cells, resulting in aggravated disease 10 . Lastly, the authors investigated the reciprocal effects of cholestatic liver disease and intestinal injury.…”

mentioning

confidence: 99%

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Bile duct-associated macrophages enter the spotlight in inflammatory cholestatic liver disease

Peiseler,

Tacke

2023

Hepatology

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Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis

Su,

He,

Wang

et al. 2024

Advanced Science

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The dynamic interplay between parenchymal hepatocytes and non‐parenchymal cells (NPCs), such as macrophages, is an important mechanism for liver metabolic homeostasis. Although numerous endeavors have been made to identify the mediators of metabolic dysfunction associated steatohepatitis (MASH), the molecular underpinnings of MASH progression remain poorly understood, and therapies to arrest MASH progression remain elusive. Herein, it is revealed that the expression of grancalcin (GCA) is upregulated in the macrophages of patients and rodents with MASH and correlates with MASH progression. Notably, the administration of recombinant GCA aggravates the development of MASH, whereas, Gca deletion in myeloid cells blunts liver steatosis and inflammation in multiple MASH murine models. Mechanistically, GCA activates macrophages via TLR9‐NF‐κB signaling, and the activated macrophages promote hepatocyte lipid accumulation and apoptosis via secretion of Interleukin‐6(IL‐6), Tumor Necrosis Factor α (TNFα), and Interleukin‐1β(IL‐1β), thereby leading to hepatic steatosis and inflammation. Finally, the therapeutic administration of antibody blocking GCA effectively halts the progression of MASH. Collectively, these findings implicate GCA as a crucial mediator of MASH and clarify a new metabolic signaling axis between the hepatocytes and macrophages, implying that GCA can emerge as a particularly interesting putative therapeutic target for reversing MASH progression.

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Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis

Cited by 43 publications

References 43 publications

Osteopontin characterizes bile duct–associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis

Osteopontin characterizes bile duct–associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis

Bile duct-associated macrophages enter the spotlight in inflammatory cholestatic liver disease

Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis

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