Treatment with an Anti-CX3CL1 Antibody Suppresses M1 Macrophage Infiltration in Interstitial Lung Disease in SKG Mice

Mizutani, Satoshi; Nishio, Juntaro; Kondo, Kanoh; Motomura, Kaori; Yamada, Zento; Masuoka, Shotaro; Yamada, Soichi; Muraoka, Sei; Ishii, Naoto; Kuboi, Yoshikazu; Sendo, Sho; Mikami, Taisei; Imai, Toshio; Nanki, Toshihiro

doi:10.3390/ph14050474

Cited by 11 publications

(6 citation statements)

References 38 publications

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“…TNF-α is a pro-inflammatory cytokine generated primarily by activated lymphocytes, macrophages, endothelial, and epithelial cells involved in the pathophysiology of ILD. TNF-α is important in the early stages and preservation of the cytokine and chemokine generation cascade and the induction of cell–cell adhesion and trans-endothelial migration [ 6 , 21 ].…”

Section: Pathogenesismentioning

confidence: 99%

Novel Biomarkers, Diagnostic and Therapeutic Approach in Rheumatoid Arthritis Interstitial Lung Disease—A Narrative Review

et al. 2022

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Rheumatoid arthritis (RA) is considered a systemic inflammatory disease marked by polyarthritis which affects the joints symmetrically, leading to progressive damage of the bone structure and eventually joint deformity. Lung involvement is the most prevalent extra-articular feature of RA, affecting 10–60% of patients with this disease. In this review, we aim to discuss the patterns of RA interstitial lung disease (ILD), the molecular mechanisms involved in the pathogenesis of ILD in RA, and also the therapeutic challenges in this particular extra-articular manifestation. The pathophysiology of RA-ILD has been linked to biomarkers such as anti-citrullinated protein antibodies (ACPAs), MUC5B mutation, Krebs von den Lungen 6 (KL-6), and other environmental factors such as smoking. Patients at the highest risk for RA-ILD and those most likely to advance will be identified using biomarkers. The hope is that finding biomarkers with good performance characteristics would help researchers better understand the pathophysiology of RA-ILD and, in turn, lead to the development of tailored therapeutics for this severe RA manifestation.

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Section: Pathogenesismentioning

confidence: 99%

Novel Biomarkers, Diagnostic and Therapeutic Approach in Rheumatoid Arthritis Interstitial Lung Disease—A Narrative Review

et al. 2022

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“…For instance, CX3CR1 + leukocytes can transmigrate into the inflamed tissue and produce proinflammatory cytokines during disease 59,60 while at the same time maintaining homeostasis in the healthy tissue. 59,[61][62][63][64][65][66] Therefore, an important finding indicates that the hypoxic environment or hypoxia signaling resulting from CCM disease 7 can affect the balance between neuroinflammation and neuroprotection 66 mediated by CX3CR1-CX3CL1 signaling. Our study suggests the links between reactive astrocytes (GFAP + , fractalkine CX3CL1 + , and its receptor CX3CR1 + cells) and CCM endothelium (PECAM1 [platelet endothelial cell adhesion molecule], CX3CL1 + cells) act as contributors that trigger immune cell recruitment (eg, microglia/monocytes, dendritic cells, neutrophils, B and CD8 cells, T regulatory lymphocytes, CX3CL1 + cells in the mouse or human [67][68][69][70][71][72] ), infiltration, and precipitate immunothrombosis in CCM lesions during mild hypoxia and chronic disease.…”

Section: Discussionmentioning

confidence: 99%

Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling

Frias-Anaya,

Gallego-Gutierrez,

Gongol

et al. 2024

ATVB

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BACKGROUND: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models. METHODS: We used genetic studies, RNA sequencing, spatial transcriptome, micro–computed tomography, fluorescence-activated cell sorting, multiplex immunofluorescence, coculture studies, and imaging techniques to reveal that sustained mild hypoxia via the CX3CR1-CX3CL1 signaling pathway influences cell-specific neuroinflammatory interactions, contributing to heterogeneity in CCM severity. RESULTS: Histological and expression profiles of CCM neurovascular lesions ( Slco1c1-iCreERT2;Pdcd10 fl/fl ; Pdcd10 BECKO ) in male and female mice found that sustained mild hypoxia (12% O 2 , 7 days) accelerates CCM disease. Our findings indicate that a small reduction in oxygen levels can significantly increase angiogenesis, neuroinflammation, and thrombosis in CCM disease by enhancing the interactions between endothelium, astrocytes, and immune cells. Our study indicates that the interactions between CX3CR1 and CX3CL1 are crucial in the maturation of CCM lesions and propensity to CCM immunothrombosis. In particular, this pathway regulates the recruitment and activation of microglia and other immune cells in CCM lesions, which leads to lesion growth and thrombosis. We found that human CX3CR1 variants are linked to lower lesion burden in familial CCMs, proving it is a genetic modifier in human disease and a potential marker for aggressiveness. Moreover, monoclonal blocking antibody against CX3CL1 or reducing 1 copy of the Cx3cr1 gene significantly reduces hypoxia-induced CCM immunothrombosis. CONCLUSIONS: Our study reveals that interactions between CX3CR1 and CX3CL1 can modify CCM neuropathology when lesions are accelerated by environmental hypoxia. Moreover, a hypoxic environment or hypoxia signaling caused by CCM disease influences the balance between neuroinflammation and neuroprotection mediated by CX3CR1-CX3CL1 signaling. These results establish CX3CR1 as a genetic marker for patient stratification and a potential predictor of CCM aggressiveness.

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“…The chemokine CX3CL1 is known to be regulated by several factors, including hypoxia, although it has never, to our knowledge, been associated with VHL loss of function or identified as a mechanism in shaping the TME in ccRCC ( 28 ). The CX3CL1/CX3CR1 axis has also been associated with driving a proinflammatory phenotype in disease settings, and administration of an anti-CX3CL1–neutralizing antibody in a model of interstitial lung disease resulted in a decrease of an M1-described inflammatory macrophage infiltration ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis

Wolf,

Madden,

Arner

et al. 2024

Journal of Clinical Investigation

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Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated hypoxia signaling and a tumor microenvironment (TME) highly enriched in myeloid and lymphoid cells. Loss of the von Hippel Lindau ( VHL ) gene is a critical early event in ccRCC pathogenesis and promotes stabilization of HIF. Whether VHL loss in cancer cells affects immune cells in the TME remains unclear. Using Vhl WT and Vhl -KO in vivo murine kidney cancer Renca models, we found that Vhl- KO tumors were more infiltrated by immune cells. Tumor-associated macrophages (TAMs) from Vhl- deficient tumors demonstrated enhanced in vivo glucose consumption, phagocytosis, and inflammatory transcriptional signatures, whereas lymphocytes from Vhl- KO tumors showed reduced activation and a lower response to anti–programmed cell death 1 (anti–PD-1) therapy in vivo. The chemokine CX3CL1 was highly expressed in human ccRCC tumors and was associated with Vhl deficiency. Deletion of Cx3cl1 in cancer cells decreased myeloid cell infiltration associated with Vhl loss to provide a mechanism by which Vhl loss may have contributed to the altered immune landscape. Here, we identify cancer cell–specific genetic features that drove environmental reprogramming and shaped the tumor immune landscape, with therapeutic implications for the treatment of ccRCC.

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Treatment with an Anti-CX3CL1 Antibody Suppresses M1 Macrophage Infiltration in Interstitial Lung Disease in SKG Mice

Cited by 11 publications

References 38 publications

Novel Biomarkers, Diagnostic and Therapeutic Approach in Rheumatoid Arthritis Interstitial Lung Disease—A Narrative Review

Novel Biomarkers, Diagnostic and Therapeutic Approach in Rheumatoid Arthritis Interstitial Lung Disease—A Narrative Review

Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling

VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis

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