RELMα Licenses Macrophages for Damage-Associated Molecular Pattern Activation to Instigate Pulmonary Vascular Remodeling

Lin, Qi; Fan, Chunling; Skinner, John; Hunter, Elizabeth; Macdonald, A; Illei, Peter B.; Yamaji-Kegan, Kazuyo; Johns, Roger A.

doi:10.4049/jimmunol.1900535

Cited by 27 publications

(31 citation statements)

References 56 publications

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“…Another PH-inducing factor, resistin-like molecule-α (RELMα) was increased in a hypoxia-induced mouse model for PH, and its human homologue, resistin, was also found to be upregulated in macrophage-like inflammatory cells in IPAH patients. In these patients, resistin-stimulated macrophages promoted the apoptosis-resistant proliferation of PASMCs [41].…”

Section: Macrophagesmentioning

confidence: 91%

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Koudstaal

Boomars

Kool

2020

JCM

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Pulmonary hypertension (PH) is a debilitating progressive disease characterized by increased pulmonary arterial pressures, leading to right ventricular (RV) failure, heart failure and, eventually, death. Based on the underlying conditions, PH patients can be subdivided into the following five groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) PH due to lung disease, (4) chronic thromboembolic PH (CTEPH), and (5) PH with unclear and/or multifactorial mechanisms. Currently, even with PAH-specific drug treatment, prognosis for PAH and CTEPH patients remains poor, with mean five-year survival rates of 57%–59% and 53%–69% for PAH and inoperable CTEPH, respectively. Therefore, more insight into the pathogenesis of PAH and CTEPH is highly needed, so that new therapeutic strategies can be developed. Recent studies have shown increased presence and activation of innate and adaptive immune cells in both PAH and CTEPH patients. Moreover, extensive biomarker research revealed that many inflammatory and immune markers correlate with the hemodynamics and/or prognosis of PAH and CTEPH patients. Increased evidence of the pathological role of immune cells in innate and adaptive immunity has led to many promising pre-clinical interventional studies which, in turn, are leading to innovative clinical trials which are currently being performed. A combination of immunomodulatory therapies might be required besides current treatment based on vasodilatation alone, to establish an effective treatment and prevention of progression for this disease. In this review, we describe the recent progress on our understanding of the involvement of the individual cell types of the immune system in PH. We summarize the accumulating body of evidence for inflammation and immunity in the pathogenesis of PH, as well as the use of inflammatory biomarkers and immunomodulatory therapy in PAH and CTEPH.

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Section: Macrophagesmentioning

confidence: 91%

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Koudstaal

Boomars

Kool

2020

JCM

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“…We then stimulated 3T3-L1 embryonic fibroblasts (ATCC® CL-173™, ATCC, Manassas, VA) with hResistin at different doses for 10 minutes and lysed the cells with Laemmli sample buffer. We analyzed the cell lysates by immunoblotting with anti-phospho-Akt [ 2 , 18 , 20 ] (#4060, Cell Signaling Technology, Danvers, MA) and anti-GAPDH (G8795, Sigma-Aldrich) to determine the activity of the purified hResistin. Western blot analysis was performed as previously described [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…We analyzed the cell lysates by immunoblotting with anti-phospho-Akt [2,18,20] (#4060, Cell Signaling Technology, Danvers, MA) and anti-GAPDH (G8795, Sigma-Aldrich) to determine the activity of the purified hResistin. Western blot analysis was performed as previously described [18]. The Trans-Blot Turbo Nitrocellulose Transfer Kit (#1704271, Bia-Rad) were used and protein bands were visualized by chemiluminescence (ECL; RPN2106, GE Healthcare, Marlborough, MA).…”

Section: Production Of Recombinant Hresistin Proteinmentioning

confidence: 99%

“…Intriguingly similarity between rodent RELMα and hResistin is not limited to their tissue and cellular sources, but also their proinflammatory and pro-proliferative functions [ 2 , 13 ]. Based on data from our lab and others, hResistin and rodent RELMα have potent mitogenic, angiogenic, vasoconstrictive, and chemokine effects in lung tissue [ 2 , 14 , 15 ], contributing etiologically to the development of pulmonary arterial hypertension (PAH) [ 13 , 16 – 18 ]. The proinflammatory properties of hResistin, and its potential to be used as a biomarker and therapeutic target of human PAH and other related cardiovascular inflammatory diseases have been widely studied.…”

Section: Introductionmentioning

confidence: 99%

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Systemic evaluation and localization of resistin expression in normal human tissues by a newly developed monoclonal antibody

et al. 2020

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Resistin and resistin-like molecules are pleiotropic cytokines that are involved in inflammatory diseases. Our previous work suggested that resistin has the potential to be used as a biomarker and therapeutic target for human pulmonary arterial hypertension. However, data are limited on the distribution of resistin in healthy human organs. In this study, we used our newly developed anti-human resistin (hResistin) antibody to immunohistochemically detect the expression, localization, and intracellular/extracellular compartmentalization of hResistin in a full human tissue panel from healthy individuals. The potential cross reactivity of this monoclonal anti-hResistin IgG1 with normal human tissues also was verified. Results showed that hResistin is broadly distributed and principally localized in the cytoplasmic granules of macrophages scattered in the interstitium of most human tissues. Bone marrow hematopoietic precursor cells also exhibited hResistin signals in their cytoplasmic granules. Additionally, hResistin labeling was observed in the cytoplasm of nervous system cells. Notably, the cytokine activity of hResistin was illustrated by positively stained extracellular material in most human tissues. These data indicate that our generated antibody binds to the secreted hResistin and support its potential use for immunotherapy to reduce circulating hResistin levels in human disease. Our findings comprehensively document the basal expression patterns of hResistin protein in normal human tissues, suggest a critical role of this cytokine in normal and pathophysiologic inflammatory processes, and offer key insights for using our antibody in future pharmacokinetic studies and immunotherapeutic strategies.

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“…Furthermore, inflammatory processes are linked to disease progression [ 8 , 16 , 20 ], and plasma levels of cyto- and chemokines such as interleukin (IL)-1β, IL-6, monocyte chemotactic protein (MCP)-1 and tumor necrosis factor (TNF)-α have prognostic value [ 3 , 21 , 39 , 42 ]). A potential source of increased circulating mediators are perivascular infiltrates of mononuclear cells that were described in the lung of PAH patients [ 9 , 29 ]. However, the molecular connection(s) between inflammation and vascular remodeling remain to be deciphered.…”

Section: Introductionmentioning

confidence: 99%

The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice

Batool¹,

Berghausen²,

Zierden³

et al. 2020

Basic Res Cardiol

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Six-transmembrane protein of prostate (Stamp2) protects from diabetes and atherosclerosis in mice via anti-inflammatory mechanisms. As chronic inflammation is a hallmark of pulmonary arterial hypertension (PAH), we investigated the role of Stamp2. Stamp2 expression was substantially reduced in the lung of humans with idiopathic PAH, as well as in experimental PAH. In Stamp2-deficient mice, hypoxia modestly aggravated pulmonary vascular remodeling and right ventricular pressure compared to WT. As endothelial cell (EC) and pulmonary arterial smooth muscle cell (PASMC) phenotypes drive remodeling in PAH, we explored the role of Stamp2. Knock-down of Stamp2 in human EC neither affected apoptosis, viability, nor release of IL-6. Moreover, Stamp2 deficiency in primary PASMC did not alter mitogenic or migratory properties. As Stamp2 deficiency augmented expression of inflammatory cytokines and numbers of CD68-positive cells in the lung, actions of Stamp2 in macrophages may drive vascular remodeling. Thus, PASMC responses were assessed following treatment with conditioned media of primary Stamp2−/− or WT macrophages. Stamp2−/− supernatants induced PASMC proliferation and migration stronger compared to WT. A cytokine array revealed CXCL12, MCP-1 and IL-6 as most relevant candidates. Experiments with neutralizing antibodies confirmed the role of these cytokines in driving Stamp2’s responses. In conclusion, Stamp2 deficiency aggravates pulmonary vascular remodeling via cross-talk between macrophages and PASMC. Despite a substantial pro-inflammatory response, the hemodynamic effect of Stamp2 deficiency is modest suggesting that additional mechanisms apart from inflammation are necessary to induce severe PAH.

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RELMα Licenses Macrophages for Damage-Associated Molecular Pattern Activation to Instigate Pulmonary Vascular Remodeling

Cited by 27 publications

References 56 publications

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Systemic evaluation and localization of resistin expression in normal human tissues by a newly developed monoclonal antibody

The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice

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