CD131 Contributes to Ulcerative Colitis Pathogenesis by Promoting Macrophage Infiltration
Curation statements for this article:-
Curated by eLife
eLife Assessment
Ulcerative colitis (UC) is a chronic gut inflammatory condition affecting the colon in humans. This study uses human samples as well as a mouse model of colitis induced by a chemical, DSS, to investigate the role of an immune marker, CD131, in UC pathogenesis. The study, as presented, is incomplete, as experimental details are lacking, the statistical analyses are deficient, and there is not yet direct evidence for a CD131-mediated mechanism of gut inflammation.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
Abstract
Ulcerative colitis (UC) is a group of chronic inflammatory bowel disease (IBD) mainly affecting the colon. The exact etiology of ulcerative colitis remains elusive. CD131 is a receptor subunit mediating the effects of hematopoietic growth factors GM-CSF and IL-3, which regulate various inflammatory responses. The pleiotropic effects of the cytokines on intestinal inflammation suggest that additional factors influence their overall function, where the receptor may play a role.In the present study, we investigated the role of CD131 in the pathogenesis of ulcerative colitis, with the use of murine colitis model established by administration of DSS in the drinking water.By comparing the immune and inflammatory responses between wt and CD131-deficient mice, we found that CD131 contributed to DSS-induced murine colitis, which functioned in synergy with tissue- infiltrating macrophages. Besides, CD131 may have promoted the chemotaxis of macrophages and T cells into the colon through CCL4. In addition, we analyzed clinical data and pathology specimens from ulcerative colitis patients and found that CD131 was associated with the endoscopic and pathological severity of intestinal inflammation.The present study provides a novel way to the understanding of the mechanisms of GM-CSF and IL-3 effects in the intestine, which will benefit the development of therapeutic approaches.
Article activity feed
-
-
-
eLife Assessment
Ulcerative colitis (UC) is a chronic gut inflammatory condition affecting the colon in humans. This study uses human samples as well as a mouse model of colitis induced by a chemical, DSS, to investigate the role of an immune marker, CD131, in UC pathogenesis. The study, as presented, is incomplete, as experimental details are lacking, the statistical analyses are deficient, and there is not yet direct evidence for a CD131-mediated mechanism of gut inflammation.
-
Reviewer #1 (Public review):
Summary:
This study investigates the role of CD131, a receptor subunit for GM-CSF and IL-3, in ulcerative colitis pathogenesis using a DSS-induced murine colitis model. By comparing wild-type and CD131-deficient mice, the authors demonstrate that CD131 contributes to DSS-induced colitis, working in concert with tissue-infiltrating macrophages.
Strengths:
The research shows that CD131's influence on macrophage and T cell chemotaxis is mediated by CCL4. The authors conclude by proposing a pro-inflammatory role for CD131 in murine colitis and suggest potential clinical relevance in human inflammatory bowel disease.
Weaknesses:
The statistical association between increased CD131 expression and clinical IBD was not observed in Table 1, indicating that the main results from animal experiments were not reproduced …
Reviewer #1 (Public review):
Summary:
This study investigates the role of CD131, a receptor subunit for GM-CSF and IL-3, in ulcerative colitis pathogenesis using a DSS-induced murine colitis model. By comparing wild-type and CD131-deficient mice, the authors demonstrate that CD131 contributes to DSS-induced colitis, working in concert with tissue-infiltrating macrophages.
Strengths:
The research shows that CD131's influence on macrophage and T cell chemotaxis is mediated by CCL4. The authors conclude by proposing a pro-inflammatory role for CD131 in murine colitis and suggest potential clinical relevance in human inflammatory bowel disease.
Weaknesses:
The statistical association between increased CD131 expression and clinical IBD was not observed in Table 1, indicating that the main results from animal experiments were not reproduced in human subjects. Additionally, due to the absence of experimental results regarding the downstream signaling pathways through CD131, it is difficult to infer the precise differentiated outcomes of this study. Furthermore, the effects of CD131 on immune cells other than macrophages were not presented, and the results specific to macrophage-selective CD131 were not shown. Therefore, I conclude that it is challenging to provide a detailed review as there is a lack of supporting evidence for the core arguments made in this paper.
-
Reviewer #2 (Public review):
Summary:
This study investigates the potential role of CD131, a cytokine receptor subunit shared by GM-CSF and IL-3, in intestinal inflammation. Using heterozygous mice with an inactivating mutation on this gene, the study demonstrates ameliorated inflammation, associated with less infiltration of macrophages. Moreover, the depletion of macrophages prevented many of the inflammatory effects of DSS and made both WT and mutant mice equivalent in terms of inflammation severity. Correlative data showing increased CD131+ cells in tissues of patients with ulcerative colitis is also demonstrating, evidence for plausibility for these pathways in human disease.
Strengths:
The phenotype of mutant mice seems quite robust and the pathways proposed, GM-CSF signaling in macrophages with CCL4 as a downstream pathway, are …
Reviewer #2 (Public review):
Summary:
This study investigates the potential role of CD131, a cytokine receptor subunit shared by GM-CSF and IL-3, in intestinal inflammation. Using heterozygous mice with an inactivating mutation on this gene, the study demonstrates ameliorated inflammation, associated with less infiltration of macrophages. Moreover, the depletion of macrophages prevented many of the inflammatory effects of DSS and made both WT and mutant mice equivalent in terms of inflammation severity. Correlative data showing increased CD131+ cells in tissues of patients with ulcerative colitis is also demonstrating, evidence for plausibility for these pathways in human disease.
Strengths:
The phenotype of mutant mice seems quite robust and the pathways proposed, GM-CSF signaling in macrophages with CCL4 as a downstream pathway, are all plausible and concordant with existing models. Many of the experiments included meaningful endpoints and were overall well performed.
Weaknesses:
(1) Experimental rigor was lacking in this manuscript, which provided limited or no details on the number of independent iterations that each experiment was done, the number of animals per group, the number of technical or biological replicates in each graph, etc.
(2) Details of animal model validation showing that this particular mutant allele results in a lack of CD131 protein expression were not shown. Moreover, since the paper uses heterozygous mice, it is critical to show that at the protein level, there is indeed reduced expression of CD131 in het mice compared to controls (many heterozygous states do not lead to appreciable protein depletion).
(3) Another major weakness is that the paper asserts a causal relationship between CD131 signaling and CCL4 production: the data shown indicates that the phenotypes of CCL4 deficiency (through Ab blockade) and CD131 partial deficiency (in het mice) are similar. However, this does not establish that CD131 signaling acts through CCL4.
(4) Lastly, while the paper claims that CD131 acts through macrophage recruitment, the evidence is circumstantial and not direct. DSS-induced acute colitis is largely mediated by macrophages, so any manipulation associated with less severe inflammation is accompanied by lesser macrophage infiltration in this model: this does not directly establish that CD131 acts directly on macrophages, which would require cell-specific knockout or complex cell reconstitution experiments.
-
