Targeted Disruption of Ig-Hepta/Gpr116 Causes Emphysema-like Symptoms That Are Associated with Alveolar Macrophage Activation

Ariestanti, Donna Maretta; Ando, Hitoshi; Hirose, Shigehisa; Nakamura, Nobuhiro

doi:10.1074/jbc.m115.648311

Cited by 21 publications

(19 citation statements)

References 63 publications

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“…The lung dysfunction occurred in an age-dependent fashion in young knockout animals. Previous models identified some transcriptionally altered genes in late embryonic lung (RyR2, [ 19 ], and inflammatory cytokines, [ 52 ]). The first regulated surfactant components were noted at one (SatPC, [ 20 ]) and two weeks (SP-A,[ 21 ]) of age.…”

Section: Discussionmentioning

confidence: 99%

Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium

et al. 2015

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Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysema-like pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.

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Section: Discussionmentioning

confidence: 99%

Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium

et al. 2015

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“…The surfactant lipid changed induced by SP-D may be attributable to its effects on alveolar type II cell activity ( 177 , 193 , 414 ). Although GPR116 deficiency also causes an emphysema-like phenotype that is associated with alveolar macrophage activation ( 177 , 416 ), the phenotypes of neither GPR116 nor Sftpd -deficient mice fully reflect those of human COPD. Mouse alveolar macrophages become foamy with lipid-laden phagosomes due to extensive uptake of surfactant lipids ( 177 , 417 , 418 ); however, in human pathology, foamy macrophages are found in diverse disorders, including diffuse pan-bronchiolitis or bronchiolitis associated with bronchiecstasis ( 419 ), diseases of surfactant homeostasis ( 420 ), extrinsic allergic alveolitis ( 421 ), and tuberculosis, rather than in COPD.…”

Section: The Role Of Sp-d In Respiratory Diseasementioning

confidence: 99%

Surfactant Protein D in Respiratory and Non-Respiratory Diseases

2018

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Surfactant protein D (SP-D) is a multimeric collectin that is involved in innate immune defense and expressed in pulmonary, as well as non-pulmonary, epithelia. SP-D exerts antimicrobial effects and dampens inflammation through direct microbial interactions and modulation of host cell responses via a series of cellular receptors. However, low protein concentrations, genetic variation, biochemical modification, and proteolytic breakdown can induce decomposition of multimeric SP-D into low-molecular weight forms, which may induce pro-inflammatory SP-D signaling. Multimeric SP-D can decompose into trimeric SP-D, and this process, and total SP-D levels, are partly determined by variation within the SP-D gene, SFTPD. SP-D has been implicated in the development of respiratory diseases including respiratory distress syndrome, bronchopulmonary dysplasia, allergic asthma, and chronic obstructive pulmonary disease. Disease-induced breakdown or modifications of SP-D facilitate its systemic leakage from the lung, and circulatory SP-D is a promising biomarker for lung injury. Moreover, studies in preclinical animal models have demonstrated that local pulmonary treatment with recombinant SP-D is beneficial in these diseases. In recent years, SP-D has been shown to exert antimicrobial and anti-inflammatory effects in various non-pulmonary organs and to have effects on lipid metabolism and pro-inflammatory effects in vessel walls, which enhance the risk of atherosclerosis. A common SFTPD polymorphism is associated with atherosclerosis and diabetes, and SP-D has been associated with metabolic disorders because of its effects in the endothelium and adipocytes and its obesity-dampening properties. This review summarizes and discusses the reported genetic associations of SP-D with disease and the clinical utility of circulating SP-D for respiratory disease prognosis. Moreover, basic research on the mechanistic links between SP-D and respiratory, cardiovascular, and metabolic diseases is summarized. Perspectives on the development of SP-D therapy are addressed.

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“…GPR116 is believed to be involved in the regulation of lung surfactant homeostasis; however, more recently GPR116-deficient alveolar macrophages were shown to display activated phenotypes with enhanced NF-κB activation and express high levels of inflammatory mediators, lipid hydroperoxides, reactive oxygen species, and MMPs. The GPR116deficient animals exhibited emphysema-like symptoms with foamy alveolar macrophages accumulating in the lung (160).…”

Section: Gpr116 (Ig-hepta)mentioning

confidence: 97%

“…Regulation of macrophage-induced inflammation (160) tissue types tested) (21). The list of enriched genes included a number of known complement and chemokine receptors such as C3aR, C5aR, Ccr2l, Ccr1, Ccr2, and Cx3cr1.…”

Section: Gpr116mentioning

confidence: 99%

G Protein-Coupled Receptors in Macrophages

Lin

Stacey

2016

Microbiol Spectr

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As the largest receptor gene family in the human genome, with >800 members, the signal-transducing G protein-coupled receptors (GPCRs) play critical roles in nearly all conceivable physiological processes, ranging from the sensing of photons and odorants to metabolic homeostasis and migration of leukocytes. Unfortunately, an exhaustive review of the several hundred GPCRs expressed by myeloid cells/macrophages (P.J. Groot-Kormelink, L .Fawcett, P.D. Wright, M. Gosling, and T.C. Kent, BMC Immunol 12:57, 2012, doi:10.1186/1471-2172-13-57) is beyond the scope of this chapter; however, we will endeavor to cover the GPCRs that contribute to the major facets of macrophage biology, i.e., those whose expression is restricted to macrophages and the GPCRs involved in macrophage differentiation/polarization, microbial elimination, inflammation and resolution, and macrophage-mediated pathology. The chemokine receptors, a major group of myeloid GPCRs, will not be extensively covered as they are comprehensively reviewed elsewhere.

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Targeted Disruption of Ig-Hepta/Gpr116 Causes Emphysema-like Symptoms That Are Associated with Alveolar Macrophage Activation

Cited by 21 publications

References 63 publications

Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium

Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium

Surfactant Protein D in Respiratory and Non-Respiratory Diseases

G Protein-Coupled Receptors in Macrophages

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