The homozygous CX3CR1-M280 mutation impairs human monocyte survival

Collar, Amanda L.; Swamydas, Muthulekha; O’Hayre, Morgan; Sajib, Sanaullah; Hoffman, Kevin W.; Singh, Satya P.; Mourad, Ahmad; Johnson, Melissa D.; Ferré, Elise M. N.; Farber, Joshua M.; Lim, Jean K.; Mikelis, Constantinos M.; Gutkind, J. Silvio; Lionakis, Michail S.

doi:10.1172/jci.insight.95417

Cited by 25 publications

(15 citation statements)

References 41 publications

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“…In CD patients, a dysfunctional CX3CR1 variant is associated with the development of intestinal stenosis and ileocolonic involvement. This mutation has been previously associated with increased risk and worse outcome of human systemic candidiasis [57] and interferes with the fractalkine-mediated survival of blood monocytes [58]. Moreover, CD patients carrying this mutation have reduced serum levels of ASCA IgG and present reduced IgG titers against a variety of fungal commensals [3].…”

Section: Introductionmentioning

confidence: 99%

Macrophage interactions with fungi and bacteria in inflammatory bowel disease

Leonardi¹,

Li²,

Iliev

2018

Current Opinion in Gastroenterology

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Purpose of the review In this review, we discuss recent advances into delineating the dual role of intestinal phagocytes in health and during intestinal disease. We further discuss the key role of gut-resident macrophages in recognition of bacterial and fungal microbiota in the gut. Recent findings Inflammatory bowel disease (IBD) commonly manifests with pathologic changes in the composition of gut bacterial and fungal microbiota. Intestinal macrophages are key regulators of the balance between tolerogenic immunity and inflammation. Recent studies have highlighted the role of resident intestinal macrophages in the control of commensal fungi and bacteria in the steady state and during dysbiosis. The dual role of these cells in maintaining intestinal homeostasis and responding to microbiota dysbiosis during inflammation is being increasingly studied. Summary It is becoming increasingly clear that an aberrant pro-inflammatory response to microbiota by infiltrating monocytes plays a role in the development of intestinal inflammation. Intestinal mononuclear phagocytes with characteristics of macrophages play an important role in limiting fungal and bacterial overgrowth under these conditions, but can be influenced by the inflammatory environment to further propel inflammation. Better understanding of the interaction of intestinal macrophages with host microbiota including commensal fungi and bacteria, provides an opportunity for the development of more targeted therapies for Inflammatory Bowel Disease.

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Section: Introductionmentioning

confidence: 99%

Macrophage interactions with fungi and bacteria in inflammatory bowel disease

Leonardi¹,

Li²,

Iliev

2018

Current Opinion in Gastroenterology

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“…Our results also suggest that consideration should be given when studying the role of monocyte subsets in human diseases using mouse models. CX3CR1 signaling is an essential survival factor for NC-Mo but not C-Mo as demonstrated by several studies [26,30,31]. Further studies are now needed to compare the intracellular signaling activity of CX3CR1 in mouse and human C-Mo and NC-Mo.…”

Section: Discussionmentioning

confidence: 98%

Mouse Classical and Non-Classical Monocytes Express Comparable Levels of Chemokine Receptor CX3CR1

Cassetta

Heideveld

Matilionyte

et al. 2020

Preprint

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Human and mouse monocytes are divided into two subpopulations, classical (C-Mo) and nonclassical (NC-Mo) monocytes. CC-chemokine receptor 2 (CCR2) and CX3C-chemokine receptor 1 (CX3CR1) are common features of monocyte subsets between humans and mice, i.e., C-Mo and NC-Mo are characterized as CCR2 high CX3CR1 low and CCR2 low CX3CR1 high . Since many studies utilize mouse models to investigate roles of monocytes in human diseases, it is important to understand the similarities and differences between human and mouse monocytic subsets.In this study, we show that the expression of Cx3cr1 mRNA and CX3CR1 cell surface protein are different between circulating monocytic subsets in human but not in mice. We analyzed monocyte subsets in the blood using wild type C57BL/6 and Cx3cr1-GFP knock-in (Cx3cr1 GFP/+ ) reporter mice. We observed higher Cx3cr1 promoter activity indicated by GFP expression in NC-Mo compared to C-Mo. However, there were no differences between the subsets in CX3CR1 mRNA nor surface protein expression determined by anti-CX3CR1 antibody or binding of fluorophore-conjugated ligand. However in the bone marrow of Cx3cr1 GFP/+ mice, CX3CR1 expression was higher in NC-Mo compared to C-Mo, suggesting that mouse NC-Mo express higher level of CX3CR1 than C-Mo in the bone but this difference disappears in the blood. In contrast, human NC-Mo differentially expressed CX3CR1 compared to C-Mo in both blood and bone marrow. Given these findings, the discrepancy between promoter activity and protein levels should be considered when the roles of CX3CR1 are investigated in mouse models of human diseases.

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“…In this exploratory population-based case-control study, we identi- CX3CL1 is a chemokine involved in immune cell recruitment and antitumor immunity, [20][21][22] but has also been implicated in cancer cell adhesion, migration, and metastasis. 23 In line with our observation, high tissue expression of CX3CL1 has previously been associated with favorable prognosis in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Circulating inflammation markers and prostate cancer

et al. 2019

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Background Chronic inflammation is thought to influence the risk of prostate cancer. The purpose of this population‐based case‐control study was to evaluate the association of 48 circulating inflammation markers with prostate cancer, to identify candidate markers for further investigation. Methods Serum samples collected from 235 prostate cancer patients and 198 population‐based controls recruited in Örebro County, Sweden, in 1989‐1991, were assessed using a multiplex bead‐based immunoassay to determine concentrations of 48 circulating inflammation markers. Logistic regression was first used to evaluate the association between individual markers (highest vs lowest concentration quartile) and prostate cancer in unadjusted and mutually adjusted models. Second, patients with inflammatory conditions, metastatic or advanced prostate cancer, were excluded to address the possible influence of systemic disease on inflammation markers. Results Individual analyses first identified 21 markers associated with prostate cancer (P < .05), which after mutual adjustment were reduced to seven markers. After the exclusion of men with conditions linked with systemic inflammation, associations between prostate cancer and deviant levels of C‐X3‐C motif chemokine ligand 1, platelet‐derived growth factor subunit B homodimer, interleukin 10, C‐C motif chemokine ligand (CCL) 21, and CCL11 remained statistically significant. Conclusions In this explorative study, we identified candidate inflammation markers of possible importance for prostate cancer pathophysiology, for further evaluation in prospective studies.

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The homozygous CX3CR1-M280 mutation impairs human monocyte survival

Cited by 25 publications

References 41 publications

Macrophage interactions with fungi and bacteria in inflammatory bowel disease

Macrophage interactions with fungi and bacteria in inflammatory bowel disease

Mouse Classical and Non-Classical Monocytes Express Comparable Levels of Chemokine Receptor CX3CR1

Circulating inflammation markers and prostate cancer

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