Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation

Larsen, Karl-Otto; Yndestad, Arne; Sjaastad, Ivar; Løberg, Else Marit; Goverud, Ingeborg Løstegaard; Halvorsen, Bente; Jia, Jizeng; Andreassen, Arne K.; Husberg, Cathrine; Jonasson, Sofia; Lipp, Martin; Christensen, Geir; Aukrust, Pål; Skjønsberg, Ole Henning

doi:10.1152/ajplung.00048.2010

Cited by 30 publications

(34 citation statements)

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“…Ϫ/Ϫ , and ASC Ϫ/Ϫ mice exposed to 3 mo of hypoxia and their controls (n ϭ 6) were stained with the endothelial cell marker von Willebrand factor and smooth muscle ␣-actin as previously described (25). The total number of peripheral arteries at alveolar duct and wall level was counted as the number of arteries positive for von Willebrand factor per 100 alveoli.…”

Section: Methodsmentioning

confidence: 99%

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Cero

Hillestad

Sjaastad

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxiainduced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-1␤, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC Ϫ/Ϫ , and NLRP3 Ϫ/Ϫ mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC Ϫ/Ϫ mice was significantly lower than in WT exposed to hypoxia (40.8 Ϯ 1.5 mmHg vs. 55.8 Ϯ 2.4 mmHg, P Ͻ 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3Ϫ/Ϫ mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-1␤ in WT and NLRP3 Ϫ/Ϫ mice, this response was absent in ASC Ϫ/Ϫ mice. Moreover, ASC Ϫ/Ϫ mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension.inflammation; innate immunity; pulmonary vasculature PULMONARY HYPERTENSION can be a life-threatening condition leading to right-sided heart failure and premature death (5, 40). The pathogenesis of the various forms of pulmonary hypertension is not fully known, and insight into disease mechanisms is important for the development of improved treatment options for this severe condition. The role and importance of inflammation and immune activation in the development of pulmonary hypertension are not fully understood; however, inflammation has emerged as an important player. Clinically, increased circulating levels of IL-1␤ and IL-18 have been observed in patients with pulmonary arterial hypertension, indicating that inflammasomes can be activated in this condition (18,41). It is well known that innate immunity is activated in response to infection. However, in the last decade, new knowledge has emerged demonstrating that inflammatory pathways can also be activated as a result of cellular stress during sterile inflammation and that these inflammatory responses involve activation of inflammasomes (27). Inflammasome...

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Section: Methodsmentioning

confidence: 99%

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Cero

Hillestad

Sjaastad

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Although mem IgD was not found in blood IgT + B cells (21), it might be possible that mem IgD is found in IgT + cells from mucosal tissues. In mammalian lungs, CCR7 regulates normal pulmonary leukocyte homeostasis because the lack of CCR7 induces pulmonary hypertension involving perivascular infiltration of B and T lymphocytes (42). The reason for this is that CCR7 not only efficiently infiltrates leukocytes to extralymphoid tissues and sites of inflammation but also mediates the exit of leukocytes from these tissues through afferent lymph vessels (43), although again, most of these studies were focused on T cells (44).…”

Section: Effect Of Vhsv Infection On the Distribution Of Ccr7 + Cellsmentioning

confidence: 99%

CCR7 Is Mainly Expressed in Teleost Gills, Where It Defines an IgD+IgM− B Lymphocyte Subset

Castro

Bromage

Abós

et al. 2014

The Journal of Immunology

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Chemokine receptor CCR7, the receptor for both CCL19 and CCL21 chemokines, regulates the recruitment and clustering of circulating leukocytes to secondary lymphoid tissues, such as lymph nodes and Peyer's patches. Even though teleost fish do not have either of these secondary lymphoid structures, we have recently reported a homolog to CCR7 in rainbow trout (Oncorhynchus mykiss). In the present work, we have studied the distribution of leukocytes bearing extracellular CCR7 in naive adult tissues by flow cytometry, observing that among the different leukocyte populations, the highest numbers of cells with membrane (mem)CCR7 were recorded in the gill (7.5 ± 2% CCR7+ cells). In comparison, head kidney, spleen, thymus, intestine, and peripheral blood possessed <5% CCR7+ cells. When CCR7 was studied at early developmental stages, we detected a progressive increase in gene expression and protein CCR7 levels in the gills throughout development. Surprisingly, the majority of the CCR7+ cells in the gills were not myeloid cells and did not express membrane CD8, IgM, nor IgT, but expressed IgD on the cell surface. In fact, most IgD+ cells in the gills expressed CCR7. Intriguingly, the IgD+CCR7+ population did not coexpress memIgM. Finally, when trout were bath challenged with viral hemorrhagic septicemia virus, the number of CCR7+ cells significantly decreased in the gills while significantly increased in head kidney. These results provide evidence of the presence of a novel memIgD+memIgM− B lymphocyte subset in trout that expresses memCCR7 and responds to viral infections. Similarities with IgD+IgM− subsets in mammals are discussed.

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“…1 DC are absent to suppress lymphocytes by anergy (6). Recently, it was demonstrated that pulmonary lymphoid neogenesis accompanies idiopathic PH (7).…”

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confidence: 99%

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

Colvin¹,

Cripe²,

Ivy³

et al. 2013

Am J Respir Crit Care Med

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Rationale: Autoimmunity has long been associated with pulmonary hypertension. Bronchus-associated lymphoid tissue plays important roles in antigen sampling and self-tolerance during infection and inflammation. Objectives: We reasoned that activated bronchus-associated lymphoid tissue would be evident in rats with pulmonary hypertension, and that loss of self-tolerance would result in production of pathologic autoantibodies that drive vascular remodeling. Methods: We used animal models, histology, and gene expression assays to evaluate the role of bronchus-associated lymphoid tissue in pulmonary hypertension. Measurements and Main Results: Bronchus-associated lymphoid tissue was more numerous, larger, and more active in pulmonary hypertension compared with control animals. We found dendritic cells in and around lymphoid tissue, which were composed of CD31 T cells over a core of CD45RA 1 B cells. Antirat IgG and plasma from rats with pulmonary hypertension decorated B cells in lymphoid tissue, resistance vessels, and adventitia of large vessels. Lymphoid tissue in diseased rats was vascularized by aquaporin-1 1 high endothelial venules and vascular cell adhesion molecule-positive vessels. Autoantibodies are produced in bronchus-associated lymphoid tissue and, when bound to pulmonary adventitial fibroblasts, change their phenotype to one that may promote inflammation. Passive transfer of autoantibodies into rats caused pulmonary vascular remodeling and pulmonary hypertension. Diminution of lymphoid tissue reversed pulmonary hypertension, whereas immunologic blockade of CCR7 worsened pulmonary hypertension and hastened its onset. Conclusions: Bronchus-associated lymphoid tissue expands in pulmonary hypertension and is autoimmunologically active. Loss of self-tolerance contributes to pulmonary vascular remodeling and pulmonary hypertension. Lymphoid tissue-directed therapies may be beneficial in treating pulmonary hypertension.Keywords: hypertension; pulmonary; lymphoid tissue; inflammation; autoimmunity Pulmonary hypertension (PH) is characterized by progressive increases in pulmonary artery pressure and pulmonary vascular resistance resulting in right ventricular failure (1). The primary histopathologic finding in PH is vascular remodeling, in which the pulmonary vasculature becomes stiff, occluded, and fibrotic (2). Vascular remodeling seems to require lung infiltration of inflammatory cells, and continual influx likely sustains a cycle of perpetual inflammation and remodeling by poorly defined mechanisms (3).The bronchovascular space is a structure that marries sterile (vasculature) and nonsterile (airway) components. Bronchusassociated lymphoid tissues (BALTs) are tertiary lymphoid organs that provide an elegant immune surveillance apparatus ensuring airway and vessel homeostatic patency. They are histologically similar to lymph nodes containing afferent lymphatic connection, B cells, T cells, antigen-presenting cells, stroma, and a vascular supply (4). The chief antigen-presenting cells in BALT are dendritic ce...

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Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation

Cited by 30 publications

References 64 publications

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

CCR7 Is Mainly Expressed in Teleost Gills, Where It Defines an IgD+IgM− B Lymphocyte Subset

Bronchus-associated Lymphoid Tissue in Pulmonary Hypertension Produces Pathologic Autoantibodies

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