Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease

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    eLife Assessment

    This valuable study investigates the role of Complement 3a Receptor 1 (C3aR) in the pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) using mouse models with specific target deletions in various cell types. While the general relevance of C3aR in inflammatory contexts has been established before, the authors provide solid evidence here that C3aR does not contribute significantly to MASLD pathogenesis in their models. The work will be of interest to colleagues studying diseases of the liver and the intersection with inflammation.

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Abstract

Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse, C3AR1 in the liver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MφKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority of C3ar1 expression in the liver. Overall, C3aR1-MφKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressing C3ar1 , has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model.

Article activity feed

  1. eLife Assessment

    This valuable study investigates the role of Complement 3a Receptor 1 (C3aR) in the pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) using mouse models with specific target deletions in various cell types. While the general relevance of C3aR in inflammatory contexts has been established before, the authors provide solid evidence here that C3aR does not contribute significantly to MASLD pathogenesis in their models. The work will be of interest to colleagues studying diseases of the liver and the intersection with inflammation.

  2. Reviewer #1 (Public review):

    Summary:

    In this paper Homan et al used mouse models of Metabolic Dysfunction-Associated Steatotic Liver Disease and different specific target deletions in cells to rule out the role of Complement 3a Receptor 1 in the pathogenesis of disease. They provided limited evidence and only descriptive results that despite C3aR being relevant in different contexts of inflammation, however, these tenets did not hold true.

    Comments on revisions:

    The revised version fulfilled my queries.

  3. Reviewer #2 (Public review):

    Summary:

    Homan et al. examined the effect of macrophage- or Kupffer cell-specific C3aR1 KO on MASLD/MASH-related metabolic or liver phenotypes.

    Strengths:

    Established macrophage- or Kupffer cell-specific C3aR1 KO mice, and showing comparable liver metabolic phenotypes between WT and macrophage-specific C3aR1KO mice in response to normal chow diet or MASH diet feeding.

    Weaknesses:

    Insufficient data showing the effects of C3aR1KO on liver macrophage phenotypes, such as hepatic macrophage profiles, macrophage activation status, etc, which are important for the development of liver steatosis and fibrosis.

  4. Author response:

    The following is the authors’ response to the original reviews.

    Public Reviews:

    Reviewer #1 (Public review):

    Summary:

    In this paper Homan et al used mouse models of Metabolic Dysfunction-Associated Steatotic Liver Disease and different specific target deletions in cells to rule out the role of Complement 3a Receptor 1 in the pathogenesis of disease. They provided limited evidence and only descriptive results that despite C3aR being relevant in different contexts of inflammation, however, these tenets did not hold true.

    Weaknesses:

    (1) The results are based on readouts showing that C3aR is not involved in the pathogenesis of liver metabolic disease.

    (2) The description of the mouse models they used to validate their findings is not clear. Lysm-cre mice - which are claimed to delete C3aR in (?) macrophages are not …

  5. eLife assessment

    This useful study investigates the role of Complement 3a Receptor 1 (C3aR) in the pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) using mouse models with specific target deletions in various cell types. While the relevance of C3aR in inflammatory contexts has been established, the authors provide helpful but incomplete evidence that C3aR does not contribute significantly to MASLD pathogenesis in their models, a claim that would require additional experiments for support.

  6. Reviewer #1 (Public review):

    Summary:

    In this paper Homan et al used mouse models of Metabolic Dysfunction-Associated Steatotic Liver Disease and different specific target deletions in cells to rule out the role of Complement 3a Receptor 1 in the pathogenesis of disease. They provided limited evidence and only descriptive results that despite C3aR being relevant in different contexts of inflammation, however, these tenets did not hold true.

    Weaknesses:

    (1) The results are based on readouts showing that C3aR is not involved in the pathogenesis of liver metabolic disease.

    (2) The description of the mouse models they used to validate their findings is not clear. Lysm-cre mice - which are claimed to delete C3aR in (?) macrophages are not specific for these cells, and the genetic strategy to delete C3aR in Kupffer cells is not clear.

    (3) …

  7. Reviewer #2 (Public review):

    Summary:

    Homan et al. examined the effect of macrophage- or Kupffer cell-specific C3aR1 KO on MASLD/MASH-related metabolic or liver phenotypes.

    Strengths:

    Established macrophage- or Kupffer cell-specific C3aR1 KO mice.

    Weaknesses:

    Lack of in-depth study; flaws in comparisons between KC-specific C3aR1KO and WT in the context of MASLD/MASH, because MASLD/MASH WT mice likely have a low abundance of C3aR1 on KCs.

    Homan et al. reported a set of observation data from macrophage or Kupffer cell-specific C3aR1KO mice. Several questions and concerns as follows could challenge the conclusions of this study:

    (1) As C3aR1 is robustly repressed in MASLD or MASH liver, GAN feeding likely reduced C3aR1 abundance in the liver of WT mice. Thus, it is not surprising that there were no significant differences in liver …

  8. Author response:

    Public Reviews:

    Reviewer #1 (Public review):

    Summary:

    In this paper Homan et al used mouse models of Metabolic Dysfunction-Associated Steatotic Liver Disease and different specific target deletions in cells to rule out the role of Complement 3a Receptor 1 in the pathogenesis of disease. They provided limited evidence and only descriptive results that despite C3aR being relevant in different contexts of inflammation, however, these tenets did not hold true.

    Weaknesses:

    (1) The results are based on readouts showing that C3aR is not involved in the pathogenesis of liver metabolic disease.

    (2) The description of the mouse models they used to validate their findings is not clear. Lysm-cre mice - which are claimed to delete C3aR in (?) macrophages are not specific for these cells, and the genetic strategy to delete C3aR …