Deficiency of FAM3D (Family With Sequence Similarity 3, Member D), A Novel Chemokine, Attenuates Neutrophil Recruitment and Ameliorates Abdominal Aortic Aneurysm Development

He, Li; Fu, Yi; Deng, Jingna; Shen, Yicong; Wang, Yingbao; Yu, Fang; Xie, Nan; Chen, Zhongjiang; Hong, Tianpei; Xiang, Peng; Li, Qingqing; Zhou, Jing; Han, Jing‐Yan; Wang, Ying; Xi, Jianzhong; Kong, Wei

doi:10.1161/atvbaha.118.311289

Cited by 42 publications

(39 citation statements)

References 52 publications

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“…FAM3D is a gut-secreted protein reported to be regulated by nutritional status with unknown function 13 . FAM3D (Fam3D) was subsequently identified as a host-derived endogenous chemotactic agonist for the G-protein coupled receptors, namely formyl peptide receptor (FPR)1 and FPR2 (mouse Fpr1 and Fpr2) 14 , suggesting its proinflammatory properties 15 . However, the role of FAM3D (Fam3D), constitutively and abundantly expressed in the gastrointestinal tract, in the homeostasis and pathological conditions in the colon remains unclear.…”

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confidence: 99%

FAM3D is essential for colon homeostasis and host defense against inflammation associated carcinogenesis

Liang

Xiang

et al. 2020

Nat Commun

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The physiological homeostasis of gut mucosal barrier is maintained by both genetic and environmental factors and its impairment leads to pathogenesis such as inflammatory bowel disease. A cytokine like molecule, FAM3D (mouse Fam3D), is highly expressed in mouse gastrointestinal tract. Here, we demonstrate that deficiency in Fam3D is associated with impaired integrity of colonic mucosa, increased epithelial hyper-proliferation, reduced anti-microbial peptide production and increased sensitivity to chemically induced colitis associated with high incidence of cancer. Pretreatment of Fam3D−/− mice with antibiotics significantly reduces the severity of chemically induced colitis and wild type (WT) mice co-housed with Fam3D−/− mice phenocopy Fam3D-deficiency showing increased sensitivity to colitis and skewed composition of fecal microbiota. An initial equilibrium of microbiota in cohoused WT and Fam3D−/− mice is followed by an increasing divergence of the bacterial composition after separation. These results demonstrate the essential role of Fam3D in colon homeostasis, protection against inflammation associated cancer and normal microbiota composition.

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confidence: 99%

FAM3D is essential for colon homeostasis and host defense against inflammation associated carcinogenesis

Liang

Xiang

et al. 2020

Nat Commun

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“…Patients with AAA demonstrate increased blood neutrophil counts and neutrophil activation marker NGAL (neutrophil gelatinase‐associated lipocalin) . Targeting neutrophils with antibodies or blocking chemokine expression necessary for neutrophil recruitment ameliorates experimental AAA formation . Here, we revealed a role of IgE in regulating neutrophil expression of CXC chemokines CXCL5 and MIP‐2α that have been shown essential to neutrophil chemoattraction .…”

Section: Discussionmentioning

confidence: 88%

“…45 Targeting neutrophils with antibodies or blocking chemokine expression necessary for neutrophil recruitment ameliorates experimental AAA formation. 7,8,14 Here, we revealed a role of IgE in regulating neutrophil expression of CXC chemokines CXCL5 and MIP-2α that have been shown essential to neutrophil chemoattraction. [46][47][48][49] That is probably why we detected many fewer neutrophils in AAA lesions from the Apoe −/− Ige −/− mice than those in Apoe −/− mice ( Figure 4B,D).…”

Section: Discussionmentioning

confidence: 89%

“…After infiltration and activation, neutrophils release pro‐inflammatory molecules such as interleukin‐6 (IL6), neutrophil‐associated proteases and extracellular traps (NETs), matrix metalloproteinases (MMP) such as MMP‐9, cysteinyl cathepsins, and myeloperoxidase to induce aortic wall inflammation, vascular cell apoptosis, and matrix degradation, leading to aortic rupture. Depletion of circulating neutrophils by using anti‐neutrophil antibody or targeting neutrophil recruitment required chemokines or adhesion molecules inhibited AAA development in aortic elastase perfusion or peri‐aortic calcium phosphate injury‐induced mouse AAA models, supporting an important role of neutrophils in AAA formation.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of immunoglobulin E protects mice from experimental abdominal aortic aneurysms

Deng

Zhang

et al. 2020

FASEB j.

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Allergic asthma with high plasma IgE levels is a significant risk factor of human abdominal aortic aneurysm (AAA). This study tests a direct role of IgE in angiotensin‐II (Ang‐II) perfusion‐ and peri‐aortic CaCl2 injury‐induced AAA in mice. In both models, IgE‐deficiency in Apoe−/−Ige−/− mice blunts AAA growth and reduces lesion accumulation of macrophages, CD4+ and CD8+ T cells, and lesion MHC class‐II expression, CD31+ microvessel growth, and media smooth muscle cell loss, compared with those from Apoe−/− control mice. Real time‐PCR reveals significant reductions in expression of neutrophil chemoattractants MIP‐2α and CXCL5 in AAA lesions or macrophages from Apoe−/−Ige−/− mice, along with reduced lesion Ly6G+ neutrophil accumulation. Consistent with reduced lesion inflammatory cell accumulation, we find significant reductions of plasma and AAA lesion IL6 expression in Apoe−/−Ige−/− mice. Immunofluorescent staining and FACS analysis show that AAA lesion neutrophils express FcεR1. Mechanistic study demonstrates that IgE induces neutrophil FcεR1 expression, activates MAPK signaling, and promotes IL6 production. This study supports a direct role of IgE in AAA by promoting lesion chemokine expression, inflammatory cell accumulation, MAPK signaling, and cytokine expression. IgE inhibition may represent a novel therapeutic approach in AAA management.

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“…FAM3D has demonstrated a high affinity for both FPR1 and FPR2 and has been implicated in playing an important role in both inflammation and GI homeostasis via FPR activation [75]. Additional studies have found that FAM3D may also be involved in the beneficial role of glucagon secretion in Type 2 diabetes, as well as the detrimental development of abdominal aortic aneurysms [76,77].…”

Section: Host-derived Fpr Ligandsmentioning

confidence: 99%

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

Krepel

Wang

2019

IJMS

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Leukocyte infiltration is a hallmark of inflammatory responses. This process depends on the bacterial and host tissue-derived chemotactic factors interacting with G-protein-coupled seven-transmembrane receptors (GPCRs) expressed on the cell surface. Formylpeptide receptors (FPRs in human and Fprs in mice) belong to the family of chemoattractant GPCRs that are critical mediators of myeloid cell trafficking in microbial infection, inflammation, immune responses and cancer progression. Both murine Fprs and human FPRs participate in many patho-physiological processes due to their expression on a variety of cell types in addition to myeloid cells. FPR contribution to numerous pathologies is in part due to its capacity to interact with a plethora of structurally diverse chemotactic ligands. One of the murine Fpr members, Fpr2, and its endogenous agonist peptide, Cathelicidin-related antimicrobial peptide (CRAMP), control normal mouse colon epithelial growth, repair and protection against inflammation-associated tumorigenesis. Recent developments in FPR (Fpr) and ligand studies have greatly expanded the scope of these receptors and ligands in host homeostasis and disease conditions, therefore helping to establish these molecules as potential targets for therapeutic intervention.

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Deficiency of FAM3D (Family With Sequence Similarity 3, Member D), A Novel Chemokine, Attenuates Neutrophil Recruitment and Ameliorates Abdominal Aortic Aneurysm Development

Abstract: Supplemental Digital Content is available in the text.

Cited by 42 publications

References 52 publications

FAM3D is essential for colon homeostasis and host defense against inflammation associated carcinogenesis

FAM3D is essential for colon homeostasis and host defense against inflammation associated carcinogenesis

Deficiency of immunoglobulin E protects mice from experimental abdominal aortic aneurysms

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

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