Inflammation: a role for NR4A orphan nuclear receptors?

2011 ◽  
Vol 39 (2) ◽  
pp. 688-693 ◽  
Author(s):  
Jason P. McMorrow ◽  
Evelyn P. Murphy
Keyword(s):  
Inflammatory Response ◽  
Nuclear Receptors ◽  
Acute Phase ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Acute Phase Proteins ◽  
Tissue Injury ◽  
Chronic Phase ◽  
Psoriatic Skin ◽  
Orphan Nuclear Receptors

Inflammation is paradoxical; it is essential for protection following biological, chemical or physical stimuli, but inappropriate or misdirected inflammation is responsible for tissue injury in a variety of inflammatory diseases. The polarization of immune cells is critical in controlling the stages of inflammatory response. The acute phase of inflammation is characterized by a T-lymphocyte:Th2 cytokine profile and involves a co-ordinated migration of immune cells to the site of injury where production of cytokines and acute-phase proteins brings about healing. However, persistent inflammation can result in inappropriate and prolonged T-lymphocyte:Th1 cytokine-mediated action and reaction of self-molecules, leading to a chronic phase in diseases such as RA (rheumatoid arthritis), Ps (psoriasis) and atherosclerosis. The inflammatory response is also controlled by activated macrophage cells, with classically activated (M1) cells producing a wide variety of pro-inflammatory mediators, while alternatively activated (M2) macrophages participate in anti-inflammatory response. Members of the NR4A subfamily (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) of orphan NRs (nuclear receptors) have emerged as key transcriptional regulators of cytokine and growth factor action in diseases affecting our aging population. As ligand-independent and constitutively active receptors, the activity of these transcription factors is tightly controlled at the level of expression, post-translational modification and subcellular localization. NR4A subfamily members are aberrantly expressed in inflamed human synovial tissue, psoriatic skin, atherosclerotic lesions, lung and colorectal cancer cells. Significantly, prolonged or inappropriate inflammatory responses contribute to the pathogenesis of these diseases. In activated cells, NR4A receptors are rapidly and potently induced, suggesting that these receptors may act as important transcriptional mediators of inflammatory signals. NR4A receptors may contribute to the cellular processes that control inflammation, playing a critical part in the contribution of chronic inflammation or they may have a protective role, where they may mediate pro-resolution responses. Here, we will review the contribution of the NR4A orphan NRs to integration of cytokine signalling in inflammatory disorders.

scholarly journals 405 Effect of Subacute Ruminal Acidosis (SARA) and Saccharomyces cerevisiae fermentation products on inflammatory responses of dairy cows

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 164-164
Author(s):  
junfei Guo ◽  
Hooman Derakshani ◽  
Ilkyu Yoon ◽  
Khafipour Khafipour ◽  
Jan C Plaizier
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Inflammatory Response ◽  
Dairy Cows ◽  
Acute Phase ◽  
Peripheral Blood ◽  
Inflammatory Responses ◽  
Acute Phase Proteins ◽  
Inflammatory Marker ◽  
Fermentation Products ◽  
Treatment Groups

Abstract Feeding high-grain diets to dairy cows increases concentrations of acute phase proteins in peripheral blood. This inflammatory response can be reduced by supplementation with Saccharomyces cerevisiae fermentation products (SCFP). It is not clear which cytokines drive this inflammatory response, which organs are inflamed, and how these processes are affected by SCFP. The objectives of this study were to investigate if grain-induced SARA increases the concentrations of the cytokines IL-1β in peripheral blood, and of the inflammatory marker myeloperoxidase (MPO) in rumen papillae of lactating dairy cows, and if these concentrations are affected by SCFP. Thirty-two lactating Holstein dairy cows were randomly assigned to four treatment groups (n = 8) that received a TMR (34.9 %DM NDF, 18.6 %DM starch) supplemented with 1) 140 g/d of ground corn (Control), 2) 126 g/d corn and 14 g/d of Diamond V Original XPCTM (XPC), 3) 121 g/d corn and 19 g/d Diamond V NutriTek® (NTL), and 4) 102 g/d corn and 38 g/d of Diamond V NutriTek® (NTH). SARA challenges were conducted during wk 5 (SARA1) and 8 (SARA2) of lactation by replacing 20% of the base TMR with pellets containing 50% barley and 50% wheat. Blood samples were taken weekly between wk 4 (preSARA1) and wk 9 (postSARA2) for the analysis of IL-1β. Rumen papillae samples were taken during wk 3 (preSARA1) and wk 9 (postSARA2) for the measurement of MPO. SCFP treatment did not affect the concentrations of IL-1β, but the SARA challenges increased this concentration moderately from 9.0 to 12.3 pg/mL (P < 0.05). The concentration of MPO did not differ between preSARA1 and postSARA2, and these concentrations were not affected by SCFP. Results suggest that IL-1β may drive the acute phase response during the SARA challenges, and that these challenges did not cause inflammation of rumen papillae.

scholarly journals Evaluation of Rat Acute Phase Proteins as Inflammatory Biomarkers for Vaccine Nonclinical Safety Studies

2020 ◽  
Vol 48 (7) ◽  
pp. 845-856
Author(s):  
William J. Reagan ◽  
Ahmed M. Shoieb ◽  
Shelli J. Schomaker ◽  
Victoria R. Markiewicz ◽  
David W. Clarke ◽  
...  
Keyword(s):  
Injection Site ◽  
Acute Phase ◽  
Time Course ◽  
Inflammatory Responses ◽  
Acute Phase Proteins ◽  
Aluminum Phosphate ◽  
Positive Control ◽  
Meso Scale Discovery ◽  
Quillaja Saponaria ◽  
Time Course Study

The objectives were to characterize the kinetics of acute phase proteins (APPs) α-2 macroglobulin (A2M), α-1 acid glycoprotein (A1AGP), and fibrinogen (FIB), and injection site macroscopic and microscopic findings following intramuscular administration of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (TDaP; Adacel); adjuvants (aluminum phosphate [AlPO4]; aluminum hydroxide, Al[OH]3; CpG/Al[OH]3; or Quillaja saponaria 21 [QS-21]); or saline to female Wistar Han rats. Intravascular lipopolysaccharide (LPS) was a positive control. Injection sites and lymph nodes were evaluated microscopically, using hematoxylin and eosin (H&E) stained sections, 48 hours postdose (HPD) and compared with APP concentrations; A2M and A1AGP were measured using Meso Scale Discovery analyzer. Fibrinogen was measured on STA Compact analyzer. In a time-course study, APP peaked at 24 or 48 HPD. In a subsequent study at 48 HPD, injection site microscopic changes included inflammation and muscle degeneration/necrosis, which was different in severity/nature between groups. The APPs were not increased in rats administered saline, Al(OH)3, or AlPO4. Fibrinogen and A1AGP increased in rats administered CpG/Al(OH)3, QS-21, or TDaP; and A2M increased in rats administered QS-21. Fibrinogen, A2M, and A1AGP increased after LPS administration. Acute phase proteins can be used to monitor inflammatory responses to adjuvants; however, some adjuvants may induce inflammation without higher APPs.

Some mechanisms regulating nutrient utilisation in livestock during immune activation: an overview

2004 ◽  
Vol 44 (5) ◽  
pp. 453 ◽  
Author(s):  
I. G. Colditz
Keyword(s):  
Fatty Acid ◽  
Inflammatory Cytokines ◽  
Acute Phase ◽  
Immune Activation ◽  
Acute Phase Proteins ◽  
Tissue Injury ◽  
Acid Synthesis ◽  
Acid Uptake ◽  
Nutrient Utilisation ◽  
Pro Inflammatory Cytokines

The pro-inflammatory cytokines, IL-1, IL-6, TNFα and IFN α/β, produced during immune activation and tissue injury, override control of nutrient utilisation by the hypothalamic-somatotropic axis. The many effects of these cytokines include induction of fever and sickness behaviour, reduced fatty acid uptake by adipose tissue, reduced protein synthesis and enhanced protein breakdown in skeletal muscle, and gluconeogenesis, increased fatty acid synthesis and synthesis of acute phase proteins in the liver. Resistance to the effects of insulin, GH and IGF-1 is induced in adipose tissues, liver and muscle, at least in part through induction by pro-inflammatory cytokines of SOCS proteins which inhibit signal transduction and activation of gene transcription via the JAK/STAT pathway. These homeorhetic changes mobilise nutrients to fuel host defence responses. While an understanding of the mechanisms contributing to the catabolic state have arisen largely from studies of sepsis, trauma and acute challenge with biological mediators of the acute phase response, recent evidence in livestock suggests that graded production of pro-inflammatory cytokines during challenge with pathogens or subclinical infection can induce an incremental reduction in nutrient accretion in products of commercial value from livestock. This relationship highlights the value of good hygiene and reduced stress to improved feed utilisation for growth.

Repair and recovery mechanisms following critical illness

2016 ◽  
Author(s):  
Geoffrey Bellingan ◽  
Brijesh V. Patel
Keyword(s):  
Critical Illness ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Structure And Function ◽  
Tissue Structure ◽  
Inflammatory Activation ◽  
Recovery Mechanisms ◽  
And Function

Inflammation is the beneficial host response to foreign challenge or tissue injury that ultimately leads to the restoration of tissue structure and function. Critical illness is associated with an overwhelming and prolonged inflammatory activation. Resolution of the inflammatory response is an active process that requires removal of the inciting stimuli, cessation of the pro-inflammatory response, a timely coordinated removal of tissue leukocyte infiltration, a conversion from ‘toxic’ to reparative tissue environment, and restoration of normal tissue structure and function. Mortality may result from deficits in these resolution mechanisms. Improved delivery of critical care through prevention of harm and removal of stimuli has already delivered significant mortality benefits. Most critically-ill patients present with uncontrolled inflammation, hence anti-inflammatory strategies ameliorating this response are likely to be too late and thus futile. Rather, strategies augmenting endogenous pathways involved in the control and appropriate curtailment of such inflammatory responses may promote resolution, repair, and catabasis. Recent evidence showing that inflammation does not simply ‘fizzle out’, but its resolution involves an active and coordinated series of events. Dysfunction of these resolution checkpoints alters the normal inflammatory pathway, and is implicated in the induction and maintenance of states such as ARDS and sepsis. Improved understanding of resolution biology should provide translational pathways to not only improve survival, but also to prevent long-term morbidity resulting from tissue damage.

Haptoglobin and serum amyloid A in milk and serum during acute and chronic experimentally induced Staphylococcus aureus mastitis

2003 ◽  
Vol 70 (4) ◽  
pp. 379-386 ◽  
Author(s):  
Ulrika Grönlund ◽  
Cecilia Hultén ◽  
Peter D. Eckersall ◽  
Caroline Hogarth ◽  
Karin Persson Waller
Keyword(s):  
Staphylococcus Aureus ◽  
Acute Phase ◽  
Serum Amyloid A ◽  
Acute Phase Proteins ◽  
Chronic Phase ◽  
Subclinical Mastitis ◽  
Serum Amyloid ◽  
Amyloid A ◽  
Healthy Control ◽  
Experimentally Induced

Local and systemic changes in the acute phase proteins, haptoglobin and serum amyloid A (SAA), were studied in six dairy cows during the acute and chronic phases of experimentally induced Staphylococcus aureus mastitis. Haptoglobin and SAA were measured in serum, and in milk from infected and healthy control udder quarters within each cow. Concentrations of haptoglobin and SAA increased rapidly in both serum and milk during the acute phase of mastitis and followed a similar pattern. Significantly raised milk concentrations of SAA were also found during chronic subclinical mastitis. Serum concentrations of SAA also tended to be higher during the chronic phase than pre-infection. Increases in milk haptoglobin and SAA were specific for the infected udder quarters. In conclusion, measurement of SAA in milk samples could be a useful tool in diagnosing mastitis.

Hepatic expression of multiple acute phase proteins and down-regulation of nuclear receptors after acute endotoxin exposure

2004 ◽  
Vol 67 (7) ◽  
pp. 1389-1397 ◽  
Author(s):  
Che Fang ◽  
Seokjoo Yoon ◽  
Niclas Tindberg ◽  
Harri A Järveläinen ◽  
Kai O Lindros ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Acute Phase ◽  
Acute Phase Proteins ◽  
Down Regulation ◽  
Hepatic Expression ◽  
Endotoxin Exposure

scholarly journals Mitochondria in Injury, Inflammation and Disease of Articular Skeletal Joints

2021 ◽  
Vol 12 ◽  
Author(s):  
James Orman Early ◽  
Lauren E. Fagan ◽  
Annie M. Curtis ◽  
Oran D. Kennedy
Keyword(s):  
Inflammatory Response ◽  
Immune Cells ◽  
Tissue Damage ◽  
Tissue Injury ◽  
Expression Profiles ◽  
Healing Process ◽  
Biological Response ◽  
Shear Stresses ◽  
Joint Injury ◽  
Joint Tissue

Inflammation is an important biological response to tissue damage caused by injury, with a crucial role in initiating and controlling the healing process. However, dysregulation of the process can also be a major contributor to tissue damage. Related to this, although mitochondria are typically thought of in terms of energy production, it has recently become clear that these important organelles also orchestrate the inflammatory response via multiple mechanisms. Dysregulated inflammation is a well-recognised problem in skeletal joint diseases, such as rheumatoid arthritis. Interestingly osteoarthritis (OA), despite traditionally being known as a ‘non-inflammatory arthritis’, now appears to involve an element of chronic inflammation. OA is considered an umbrella term for a family of diseases stemming from a range of aetiologies (age, obesity etc.), but all with a common presentation. One particular OA sub-set called Post-Traumatic OA (PTOA) results from acute mechanical injury to the joint. Whether the initial mechanical tissue damage, or the subsequent inflammatory response drives disease, is currently unclear. In the former case; mechanobiological properties of cells/tissues in the joint are a crucial consideration. Many such cell-types have been shown to be exquisitely sensitive to their mechanical environment, which can alter their mitochondrial and cellular function. For example, in bone and cartilage cells fluid-flow induced shear stresses can modulate cytoskeletal dynamics and gene expression profiles. More recently, immune cells were shown to be highly sensitive to hydrostatic pressure. In each of these cases mitochondria were central to these responses. In terms of acute inflammation, mitochondria may have a pivotal role in linking joint tissue injury with chronic disease. These processes could involve the immune cells recruited to the joint, native/resident joint cells that have been damaged, or both. Taken together, these observations suggest that mitochondria are likely to play an important role in linking acute joint tissue injury, inflammation, and long-term chronic joint degeneration - and that the process involves mechanobiological factors. In this review, we will explore the links between mechanobiology, mitochondrial function, inflammation/tissue-damage in joint injury and disease. We will also explore some emerging mitochondrial therapeutics and their potential for application in PTOA.

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