Posts Tagged: inflammation

Autophagy and Mitophagy in Cardiovascular Disease

Autophagy and Mitophagy in Cardiovascular Disease

José Manuel Bravo-San Pedro, Guido Kroemer, Lorenzo Galluzzi

Detrimental effects of autophagy or mitophagy inhibition on cardiovascular health. Multiple genetic interventions that limit autophagic or mitophagic flux at the whole-body level or in specific compartments of the cardiovascular system have been associated with the spontaneous development of cardiovascular disorders. AP indicates autophagosome; APL, autophagolysosome; Atg5, autophagy related 5; Bnip3l, BCL2 interacting protein 3 like; Dnml1, dynamin 1 like; Fbxo32, F-box protein 32; L, lysosome; Lamp2, lysosomal-associated membrane protein 2; Mfn1, mitofusin 1; Park2, Parkinson disease (autosomal recessive, juvenile) 2, parkin; Pink1, PTEN-induced putative kinase 1; Sirt6, sirtuin 6; Tfrc, transferrin receptor; and Trp53, transformation-related protein 53. [Powerpoint File]

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Xiaoming Hu, T. Michael De Silva, Jun Chen, Frank M. Faraci

Structural alterations in endothelial cells are critical for blood–brain barrier (BBB) opening early after ischemic stroke. A, The opening of paracellular pathways: cytoskeletal rearrangements and related signaling in endothelial cells. B, The transcellular pathway of BBB leakage. ADF indicates actin-depolymerizing factor; CaM, calmodulin; LIMK, LIM kinase; MLC, myosin light chain; MLCK, MLC kinase; MLCP, MLC phosphatase; MMP, matrix metallopeptidase; ROCK: Rho kinase; TESK1, testicular protein kinase 1; and ZO, zonula occluden. [Powerpoint File]

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Xiaoming Hu, T. Michael De Silva, Jun Chen, Frank M. Faraci

Pericytes play multifaceted roles in ischemia and reperfusion. Pericytes display both beneficial and detrimental functions during ischemia and reperfusion phases, and contribute significantly to the blood–brain barrier damage and repair. 1. Pericyte contraction and dilation regulate cerebral blood flow in the ischemic and perilesion areas. 2. Pericyte protects other neurovascular unit (NVU) components through releasing protective/trophic factors such as nerve growth factor (NGF), neurotrophin-3 (NT-3), vascular endothelial growth factor (VEGF), angiopoietin (Ang-1), and glial cell line-derived neurotrophic factor (GDNF). 3. Phagocytotic pericytes help to eliminate dead or injured tissue in the ischemic core, which in turn mitigates local inflammation and reduce secondary tissue damage. 4. Pericyte–endothelial cell interaction promotes angiogenesis after stroke. 5) Pericytes have the potential to serve as an origin of NVU components during tissue repair after ischemic stroke. Illustration credit: Ben Smith. [Powerpoint File]

Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis

Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis

Marc R. Dweck, Elena Aikawa, David E. Newby, Jason M. Tarkin, James H.F. Rudd, Jagat Narula, Zahi A. Fayad

The link between inflammation, microcalcification, and macrocalcification. A large necrotic core, a thin fibrous cap, and an intense inflammation are key precipitants of acute plaque rupture and myocardial infarction. Intimal calcification is thought to occur as a healing response to this intense necrotic inflammation. However, the early stages of microcalcification (detected by 18F-fluoride positron emission tomography) are conversely associated with an increased risk of rupture. In part, this is because of residual plaque inflammation and in part because microcalcification itself increases mechanical stress in the fibrous cap further increasing propensity to rupture. With progressive calcification, plaque inflammation becomes pacified and the necrotic core walled off from the blood pool. The latter stages of macrocalcification (detected by computed tomographic) are, therefore, associated with plaque stability and a lower risk of that plaque rupturing (Illustration credit: Ben Smith). [Powerpoint FIle]

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E. Otterbein*, Roberta Foresti*, Roberto Motterlini*

Schematic representation of the heme oxygenase pathway. Heme, either derived from intracellular sources, such as hemoproteins and mitochondria, or from damaged tissues and red blood cell hemolysis (extracellular sources) is used by heme oxygenase enzymes (HO-1 and HO-2) to generate carbon monoxide (CO), biliverdin, and iron. Biliverdin is converted to bilirubin by biliverdin reductase (BVR), whereas iron is stored in the ferritin protein. Although heme oxygenase enzymes were initially localized in the endoplasmic reticulum, recent reports suggest that HO-1 can be found under certain conditions in other cellular compartments such as the nucleus.19 [Powerpoint File]

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E. Otterbein*, Roberta Foresti*, Roberto Motterlini*

Interaction of carbon monoxide (CO) with mitochondria. CO at high concentrations is known to inhibit mitochondrial respiration by competing with oxygen for the binding to cytochrome c oxidase (complex IV). In contrast, controlled delivery of CO gas and CO-releasing moleculess at nontoxic concentrations can protect cardiac tissue by promoting mitochondrial biogenesis, uncoupling activity, and metabolic switch (see text for details). The molecular mechanism(s) underlying these effects remains to be defined. However, the interaction of CO with mitochondrial targets different from cytochrome c oxidase is likely as the electron transport chain contains other heme-complexes that may display distinct sensitivities to CO. ROS indicates reactive oxygen species. [Powerpoint File]

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E. Otterbein*, Roberta Foresti*, Roberto Motterlini*

Heme release and cardiac repair. Ischemia-reperfusion injury leads to the sudden release of cellular contents including heme, mitochondrial DNA, and ATP. These cellular danger-associated molecular patterns (DAMPs) have each been shown to induce heme oxygenase-1 (HO-1). HO-1 expression and the subsequent generation CO, biliverdin (BV), and bilirubin (BR) target a variety of cell types that impact cellular repair and tissue regeneration. [Powerpoint File]

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

Sumanth D. Prabhu, Nikolaos G. Frangogiannis

Toll-like receptor (TLR) and nucleotide-binding oligomerization domain–like receptor (NLR) signaling. Danger-associated molecular patterns (DAMPs) released from necrotic and damaged cells and extracellular matrix bind to the TLRs, which comprised an extracellular leucine-rich repeat (LRR) domain, a transmembrane (TM) domain, and a conserved cytoplasmic Toll/interleukin (IL)-1R (TIR) domain, which serves as docking site for other TIR-containing cytoplasmic adaptor proteins (top left). The binding of DAMPs, and often coreceptors such as CD14 and MD2, to TLR4 engages the adaptor myeloid differentiation factor 88 (MyD88) via the adaptor TIR domain-containing adaptor protein (TIRAP). MyD88 recruits IL-1R–associated kinase (IRAK) 4 and the IRAK1/2 and TNF receptor associated factor (TRAF) 6 complex, which activates transforming growth factor activated kinase 1 (TAK1). TAK1, a mitogen-activated protein kinase (MAPK) KK, then activates the MAPK cascade and also phosphorylates IκB kinase (IKK), that leads to nuclear factor-κB (NF-κB) p65 and p50 nuclear translocation and the transcription of a panel of inflammatory genes, including cytokines, chemokines, cell adhesion molecules, and complement factor B. Furthermore, after endocytosis, TLR4 signals in a MyD88-independent manner via the cytoplasmic adaptor TRIF, in turn recruited through the bridging adaptor TRAM. This pathway results in noncanonical IKK and NF-κB activation, as well as the induction of type I interferon (IFN) via TANK-binding kinase (TBK) 1 and the transcription factor IFN-regulatory factor (IRF) 3. Except for TLR3, the other TLRs also signal, directly or indirectly as depicted, via MyD88. Endolysosomal TLR3 activates IRF3 signaling via TRIF and TBK1, whereas endolysosomal TLR7/8 and TLR9 also induce type I IFN via TRAF3 and IRF7 in a MyD88-dependent manner (not pictured). In addition to TLRs, intracellular NLRs respond to a variety of DAMPs via the formation of multiprotein inflammasomes, comprised an activated NLR protein, the adaptor protein apoptosis speck-like protein containing a caspase-recruitment domain (ASC), and procaspase-1. One proposed model of NLRP3 inflammasome activation results from stimulation of the purinergic P2X7 ion channel by extracellular ATP, resulting in K+ efflux, recruitment of the pannexin-1 pore, DAMP entry into cytosol, and activation of NLRP3. This activates caspase-1, which then converts pro–IL-18 and pro–IL-1β to active IL-18 and IL-1β. As discussed in the text, cell-type–specific innate immune signaling can result in distinctive, and sometimes divergent, in vivo physiological responses during acute MI. Schema derived from Mann,13 Newton and Dixit,14 Schroder and Tschopp,18 Chao,76 and Mann83 (Illustration credit: Ben Smith). [Powerpoint File]

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

Sumanth D. Prabhu, Nikolaos G. Frangogiannis

Cellular effectors and molecular signals that repress and resolve inflammation after myocardial infarction leading to the transition from the inflammatory to the proliferative phase of cardiac repair. Recruitment of anti-inflammatory monocyte (Mo) subsets (1), T-cell subpopulations, such as regulatory T cells (Tregs) (2) and invariant Natural Killer T cells (iNKT; 3) contributes to repression of the postinfarction inflammatory response. Moreover, members of the transforming growth factor (TGF)-β family (such as TGF-β1 and growth differentiation factor (GDF)-15 inhibit neutrophil transmigration by attenuating expression of adhesion molecules by endothelial cells (ECs) (4). Recruitment of pericytes (P) by microvascular ECs is mediated through platelet-derived growth factor (PDGF) receptor-β actions and may also contribute to suppression of postinfarction inflammation (5). Macrophages (Ma) acquire an anti-inflammatory phenotype, secreting TGF-β, interleukin (IL)-10, and proresolving lipid mediators, on ingestion of apoptotic neutrophils (aN) (6). Dendritic cells (DCs) are also activated after infarction and secrete anti-inflammatory cytokines (7). Cardiomyocytes (CM) in the border zone may contribute to suppression and spatial containment of the postinfarction inflammatory response by secreting mediators that promote an anti-inflammatory macrophage phenotype (such as regenerating islet-derived-3β [Reg-3β]; 8). Fibroblasts (F) also exhibit dynamic phenotypic alterations that mark the transition from the inflammatory to the proliferative phase (9). During the inflammatory phase, inflammatory cytokines (such as IL-1β and TNF-α) and activation of toll-like receptor (TLR)–dependent signaling by matrix fragments may activate a proinflammatory fibroblast phenotype. Stimulation of fibroblasts with IL-1β induces matrix metallproteinase expression and chemokine synthesis, while reducing α-smooth muscle actin levels. During the proliferative phase, activation of TGF-β–dependent cascades stimulates a matrix-preserving myofibroblast (MF) phenotype. [Powerpoint File]

Circadian Influence on Metabolism and Inflammation in Atherosclerosis

Circadian Influence on Metabolism and Inflammation in Atherosclerosis

Cameron S. McAlpine, Filip K. Swirski

Circadian influence on atherosclerosis. Circadian rhythms influence the supply of leukocytes and lipids in the circulation and the behavior of endothelial cells, smooth muscle cells, and macrophages in the vessel wall. Together, these systemic factors and local cellular events mediate atherosclerosis. HSC indicates hematopoietic stem cell. [Powerpoint File]

Chronic Heart Failure and Inflammation: What Do We Really Know?

Chronic Heart Failure and Inflammation: What Do We Really Know?

Sarah A. Dick, Slava Epelman

Suppression of ongoing inflammation in heart failure (HF). The resolution of inflammation in chronic HF has been proposed to be an active process. Clinical trials and animal models of chronic HF have shown some success from stem cell transplants involving mesenchymal stem cells, cardiac progenitor cells, and cardiosphere-derived cells. The beneficial effect is autocrine in nature and likely involved cardiac macrophages; however, the mechanism is still not know. There is some evidence to suggest a role for colony-stimulating factor 1 (CSF-1) in mediating the survival of cardiac macrophages and perhaps other, as of yet identified, cytokines that promote an anti-inflammatory phenotype. This phenotype is also known to be induced by phagocytosis of dying cells, contributing to the expression of anti-inflammatory cytokines, such as interleukin (IL)-10. [Powerpoint File]

Chronic Heart Failure and Inflammation: What Do We Really Know?

Chronic Heart Failure and Inflammation: What Do We Really Know?

Sarah A. Dick, Slava Epelman

Regulation of chronic inflammation in heart failure (HF). Expression of inflammatory cytokines in chronic HF may arise from several mechanisms. Activation of cardiomyocytes may occur in response to damage-associated molecular patterns (DAMPs; eg, HSP60 [heat shock protein 60], HMGB1 [high-mobility group box 1]) in the extracellular space released by immune cells (macrophages/monocytes), splenocytes or stressed/necrotic cardiomyocytes. Signal in response to DAMPs in chronic HF is via Toll-like receptor 4 (TLR4) that activates the NOD-like receptor family pyrin domain–containing protein 3 (NLRP3) inflammasome leading to the release of proinflammatory cytokines. The NLRP3 inflammasome can also be activated in response to oxidative stress and reactive oxygen species (ROS) production in the setting of diabetes mellitus. Proinflammatory cytokines can be released in response to free mitochondrial DNA (mtDNA) from damaged mitochondria via TLR9 signaling, in the presence of impaired mitophagy. The inflammatory state drives macrophage recruitment (in an monocyte chemoattractant protein 1 [MCP-1]–dependent manner), which can further participate in the release of these cytokines. Cardiac macrophages are also responsible for the recruitment/differentiation of myofibroblasts driving cardiac fibrosis in the setting of chronic HF. This is suggested to be transforming growth factor (TGF)-β–dependent, yet remains to be conclusively demonstrated in animal models of chronic HF (represented by the dashed arrow). IL indicates interleukin; and TNF, tumor necrosis factor. [Powerpoint File]

Inflammatory Disequilibrium in Stroke

Inflammatory Disequilibrium in Stroke

Danica Petrovic-Djergovic*, Sascha N. Goonewardena*, David J. Pinsky

Inflammatory disequilibrium after stroke. After brain ischemia, circulating cells such as neutrophils, monocytes (innate immune cells), T cells (adaptive immune cells) interact with platelets, causing sludging and cessation of cerebral blood flow and tissue hypoxia. Acute ischemia refers to the early phases (minutes to hours) and delayed refers to late phases of the ischemic process (hours to days). Endothelial cell activation promotes immune cell transmigration into the injured brain parenchyma. In acute phase of brain ischemia, infiltrating immune cells (neutrophils, monocytes, dendritic cells, and T cells) and resident brain cells (microglia and astrocytes) are activated and promote tissue injury. Activated monocytes adhere to activated endothelium and after transmigration into the brain tissue transform into the blood-borne macrophages. Macrophages generate reactive oxygen intermediates, secrete proinflammatory cytokines, upregulate costimulatory molecules (CD80 shown here), and create a prothrombotic environment. Similarly, microglia migrates toward the lesion site early on after the insult and secretes proinflammatory mediators that cause additional injury; however, microglia promotes tissue repair and remodeling through debris phagocytosis. Astrocytes can secrete both proinflammatory (CXC-chemokine ligand [CXCL10], monocyte chemoattractant protein-1 [MCP-1]) as well anti-inflammatory (interleukin [IL]-10, transforming growth factor-β [TGF-β]) chemokines/cytokines to promote injury or repair, respectively; IL-23 produced by macrophages/microglia activate γδT-cells, which contributes to tissue injury via secretion of IL-17; Naïve T-cells (CD4/CD8) contribute to brain injury in an antigen unspecific manner, possibly via interferon-γ (INF-γ), reactive oxygen species (ROS), and perforin. Other T cells such as T-regulatory cells (T-regs) induce brain tissue repair via IL-10 secretion, inhibition of the effector T-cells response, neurogenesis, and central nervous system (CNS) tissue antigen tolerization. In the delayed phase after brain ischemia, antigen-presenting cells (APC), that is, macrophages, microglia, astrocytes, and dendritic cells (not depicted in the schematic), present CNS antigens to CD4+ or CD8+ T cells in antigen-specific manner in context of major histocompatibility complex (MHC) class I or II. Purinergic mediators such as ATP and adenosine act as an extracellular danger signals differentially influencing immune responses in stroke. Ectoenzymes, cluster of differentiation 39 (CD39), and cluster of differentiation 73 (CD73) act in tandem to dissipate proinflammatory and generate anti-inflammatory mediators. Brain resident cells and certain immune cells express these ectoenzymes. ICAM indicates intercellular adhesion molecule-1; MMP, matrix metalloproteinases; mo-MФs, monocytes–macrophages; and NET, neutrophil extracellular trap. [Powerpoint File]

Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology

Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology

Brian E. Sansbury, Matthew Spite

Biological actions of resolvins and other specialized proresolving lipid mediators (SPMs) related to cardiovascular inflammation. During acute inflammation or infection, SPMs are generated during leukocyte–endothelial interactions and directly block polymorphonuclear neutrophil (PMN) chemotaxis. By directly targeting the endothelial cells (ECs) of the vasculature (eg, postcapillary venules), SPMs also prevent the capture, rolling, and adhesion of PMN to the endothelial monolayer and block their extravasation across the endothelium. In addition, they stimulate production of nitric oxide (NO) and prostacyclin (PGI2) from EC. In the tissue, SPMs promote the protective actions of leukocytes by enhancing the phagocytosis of bacteria and cellular debris and macrophage efferocytosis of apoptotic PMN. In the context of atherosclerosis, SPMs decrease EC production of leukocyte chemoattractants and adhesion molecules, potentially halting further recruitment of leukocytes to the vessel wall. They also potently prevent platelet aggregation and thrombosis. In the subendothelium, enhanced macrophage efferocytosis and promotion of a resolving macrophage phenotype contributes to a more stable plaque with decreased necrosis. During pathological inward remodeling (ie, restenosis), SPMs combat neointimal hyperplasia by inhibiting vascular smooth muscle cell (VSMC) proliferation and migration while simultaneously preventing monocyte adhesion and inflammatory signaling. IL indicates interleukin; and MCP, monocyte chemoattractant protein. [Powerpoint File]

Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology

Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology

Brian E. Sansbury, Matthew Spite

The coordinated temporal events of self-limited acute inflammation. The ideal outcome of an acute inflammatory response is complete resolution. The inflammatory response can be divided into 2 general phases: initiation and resolution. Critical to progressing from initiation to resolution is the temporal switch in lipid mediators that are biosynthesized by leukocytes in the tissue, a process known as lipid mediator class switching. The earliest stage of the inflammatory response is marked by tissue edema caused by increased blood flow and microvascular permeability and is mediated by the release of proinflammatory lipid mediators including the cysteinyl leukotrienes and prostaglandins. Polymorphonuclear neutrophils (PMN) infiltrate in response to lipid mediators including leukotriene B4 and engulf and degrade pathogens. Subsequently, PMN undergo apoptosis and also switch from releasing proinflammatory mediators to proresolving mediators (eg, resolvins) that signal the clearance of apoptotic cells by macrophages (MΦ) in an anti-inflammatory process termed efferocytosis. In addition to promoting efferocytosis, proresolving lipid mediators halt further PMN recruitment and stimulate a proresolving macrophage phenotype that is important for tissue repair. [Powerpoint File]