Inflammation—Dysregulated inflammatory response and strategies for treatment

Inflammation is a natural protective response to microbial infections and tissue injury. It functions to eliminate harmful stimuli and to repair damaged tissue. The inflammatory response is initiated by different inducers of exogenous and endogenous origin. Exogenous inducers can be microbial (pathogen-associated molecular patterns [PAMPs] and virulence factors) or non-microbial (allergens, irritants, foreign bodies and toxic compounds). Endogenous inducers are produced as signals against stress or damage (cell derived, tissue derived, plasma derived or extracellular matrix derived signals)1 and under normal conditions located intracellular or integrated in the extracellular matrix. Furthermore, they can initiate a sterile inflammation. Under necrotic conditions, triggers of sterile inflammation are released into the extracellular space (for example, nuclear proteins [high-mobility group box 1], mitochondrial DNA and peptides, uric acids, cellular chaperones [heat shock proteins] and hyaluronan).2 Macrophages and mast cells mediate the initial recognition inflammatory stimuli via specific receptors of the innate immune system. As a result, numerous inflammatory mediators like chemokines, cytokines and eicosanoids are produced. A successful outcome of inflammation is the elimination of the noxious stimuli and infection. A dysregulated inflammation can become harmful and healthy cells may be damaged. As a result, further inflammatory responses are activated, which can lead to organ failure and sepsis.1 Sepsis is defined as “life-threatening organ dysfunction by a dysregulated host response to infection.”3 This short report should describe the mechanism of inflammation and dysregulated inflammatory responses. Furthermore, it highlights new developments in research to prevent and treat an uncontrolled inflammatory response, published in Acta Physiologica. The inflammatory response is initiated through the activation of a complex of transcriptional pathways. As a result, different sets of transcription factors can be activated. Transcription factors which are involved in inflammatory responses are, for example, nuclear factor of the κ light chain enhancer of B cells (NF-κB), interferon regulatory factors (IRFs), signal transducers and activators of transcription (STAT) and activator protein1 (AP-1).4 To decrease the intensity of an (uncontrolled) inflammation, it is possible to regulate the signalling pathways of transcription factors through inhibitors. NF-κB regulates the synthesis and expression of numerous proinflammatory molecules. Inactivated NF-κB in the cytoplasm is masked by the Inhibitor of kappa B (IκB) and, therefore, an increased expression of IκB is associated with the reduced NF-κB activation. During a local inflammation in acute pancreatitis (AP), NF-κB activation plays a key role in contributing to pancreatic injury and a systemic inflammatory response. The level of NF-κB activation correlates with the severity of AP. Najenson et al showed that atrial natriuretic peptide (ANP) increases the expression of IκB and reduces NF-κB activation by inhibiting nuclear translocation. As a result, ANP reduces intrapancreatic tumour necrosis factor (TNF) activity. ANP significantly suppresses the course of acute pancreatitis by reducing the inflammatory response and stimulating apoptosis. ANP may have anti-inflammatory properties by inhibiting the synthesis and release of proinflammatory cytokines.5 Another protein which is supposed to inhibit NF-κB activation is Interferon-induced protein 35 (IFI35). IFI35 is induced by the proinflammatory cytokine Interferon-γ (IRFγ), which is highly expressed in atherosclerotic lesions and functions as a mediator during the development and progression of atherosclerosis. Jian et al demonstrated that IFI35 inhibits endothelial cell proliferation, migration and the re-endothelialization of injured arteries by suppressing the nuclear translocation and activation of NF-κB. IFI35 might be a valuable target for the treatment of re-endothelialization, hyperplasia and atherosclerosis after endothelial injury.6 The secretion of type I interferons and proinflammatory cytokines is regulated by the signalling protein Stimulator of interferon genes (STING). STING pathway and its activation can lead to an effective immune response against viral and bacterial infection and is initiated by the recognition of cytosolic nucleic acids. After activation, it initiates the secretion of proinflammatory cytokines and type I interferons. Nonetheless, it is supposed that the activation of STING promotes the development of various diseases like autoimmune and inflammation-associated diseases because STING is involved in uncontrolled inflammation and its signalling is significantly upregulated in sepsis. A pharmacologic inhibition of STING signalling could therapeutically modulate the DNA-induced hyper-inflammatory response in sepsis.7 The first line of defence against pathogens is performed by anatomical and physiological barriers of the body. Damaged anatomical and physiological barriers facilitate pathogen invasion and are associated with an increased susceptibility to infections.8 The vascular endothelium builds a barrier between the blood and surrounding tissue. This barrier forms a dynamic structure to control the exchange of fluids and solutes by coordinating the opening and closing of cell junctions. The function of the endothelial barrier is regulated by inflammatory mediators and permeability increasing reagents. Endothelial barrier breakdown and uncontrolled opening and closing of cell junctions are associated with multi-organ failure in inflammation. The endothelial surface glycocalyx (ESG) covers the junctions in the interendothelial cleft. The ESG is important for the functional properties of the vascular barrier. Damaged ESG is associated with TNFα-induced inflammation, endotoxaemia, trauma and ischaemia reperfusion.9 Ischaemia and sepsis further can promote disadvantages in the glycocalyx. Disruptions in the glycocalyx can increase the access of leucocytes to endothelial adhesion molecules which in turn results in injury. Dysbalances in the functions of the endothelial cells, for example, disturbance in microvascular flow, can lead to the development of acute kidney injury.10 Acute kidney injury (AKI) is mainly caused by renal tissue hypoperfusion and hypoxia. AKI is characterized by the rapidly progressing loss of renal function within hours to days. During AKI, renal ischaemia and reperfusion injury lead to renal tubular and endothelial cell necrosis, apoptosis and inflammation. Identifying biomarkers to get an early diagnosis of AKI is a big challenge in clinical therapy.11 The standard diagnostics for the detection of AKI are based on monitoring the urinary output and serum creatinine concentration. Various biomarkers of AKI, which are associated with structural damage to the kidney, have been discovered to improve the early detection of AKI. Neutrophil gelatinase-associated lipocalin (NGAL), Kidney injury molecule 1 (KIM-1), Liver-type fatty acid-binding protein (L-FABP) and Interleukin-18 (IL-18) are biomarkers for AKI.12 One possible pathomechanism for the development of AKI is sepsis-induced organ dysfunction.11 Septic AKI is characterized by a disturbed function and organ damage. In experimental studies of septic AKI, it is reported that after treatment with endotoxin global renal blood flow was decreased.13 During sepsis, invading pathogens and their products are recognized by pattern recognition receptors (PRRs) like Toll-like receptors (TLRs). TLR4 is the best-characterized TLR and expressed in the kidney. During Gram-negative sepsis, TLR4 gets activated. As a result, renal leucocyte infiltration is initiated and proinflammatory cytokines and chemokines are released and involved in the development of sepsis-induced AKI. Thus, TLR4 activation leads to renal injury and dysfunction. It was supposed that blocking TLR4 during sepsis has beneficial survival effects and therefore inhibition of TLR4 signalling is one possibility to prevent or treat sepsis-induced AKI.14 During endotoxemia, TLR4 activation causes acute renal failure as a result of rapid release of TNFα. TLR4 stimulation is thought to initiate an inflammatory response resulting in a reduced autoregulatory capability. The regulation of stable renal blood flow and glomerular capillary pressure is controlled by afferent arterioles by autoregulation. Loss of renal autoregulation is associated with chronic kidney disease and renal failure. Van Beusecum et al hypothesize that TLR4 activation impairs afferent arteriole autoregulatory behaviour in part by stimulating oxidative stress. The authors found that an acute LPS stimulation increases renal TLR4 expression and impairs afferent arteriole autoregulatory behaviour. Inhibition of TLR4 activation with a competitive TLR4 antagonist during acute LPS treatment prevented upregulation of renal vascular TLR4 protein expression and preserved autoregulatory behaviour.15 The autonomic nervous system, especially the parasympathetic innervation, plays a major role in immune homeostasis. Locally released inflammatory mediators are able to activate sensory nerves and send signals to the nervous system. The vagus nerve influences the immune system through a pivotal anti-inflammatory pathway, the cholinergic anti-inflammatory pathway. Meroni et al describe that an increased sympathetic tone and a decreased vagal tone are associated with a higher risk of chronic inflammatory disorders. Cholinergic anti-inflammatory pathway could either be activated pharmacologically or by stimulation of the vagus nerve by application of electrical pulses. Electrical activation of the vagus nerve improved survival (during a model of sepsis) by increased release of TNFα through the spleen. Only in an intact and innervated spleen, the vagus nerve is able to exert its anti-inflammatory effect. The concept of the activation of the cholinergic anti-inflammatory pathway seems to be a new approach in the treatment of inflammatory bowel disease.16 Neuronal activity can be modulated by proinflammatory cytokines, for instance the activity of paraventricular nucleus sympathetic output. Excessive production of proinflammatory cytokines in the periphery and the brain are associated with the development of hypertension. Orexin A is supposed to be involved in the regulation of sympathetic nerve activity and blood pressure. Fan et al hypothesize that upregulated orexin A signalling in the paraventricular nucleus (PVN) increases sympathetic nerve activity (SNA) through stimulating the expression of proinflammatory cytokines. This results in an excessive production of proinflammatory cytokines, which in turn increases sympathetic outflow and leads to high blood pressure.17 Fan et al found out that the activation of Orexin A-orexin 1 receptor signalling results in increased levels of the proinflammatory cytokines interleukin-6 (IL-6) and TNFα. The authors describe an interesting model to investigate the neuro-inflammation-driven hypertension hypothesis.18 The kidney function is controlled by the sympathetic nerves. Dysregulation like chronic renal sympatho-excitation can lead to the development of hypertension with an increased risk for heart failure and chronic renal diseases. A chronic sympatho-excitation can potentially be initiated by inflammatory chemokines which interact with the central nervous system and peripheral afferent nerves and potentially increase sensory input to the kidney. So there is an evidence that the activation of the immune system and hypertension are related.19 Sympatho-excitation could also be triggered by a high-fat diet. Khan et al describe in their study how obesity induces inflammatory injury in the kidney. Obesity is comparable to a low-grade inflammation in which circulating inflammatory adipokines and cytokines (TNFα and IL-6) activate the immune system. It was shown that rats with a high-fat diet develop an increased renal expression of TNFα and IL-6 and lipid accumulation in the kidney. This is associated with an increased risk of chronic kidney disease. A high-fat diet promotes the development of adiposity and renal hyperfiltration which is associated with sympatho-excitation and an increased level of circulating and renal inflammatory cytokines. These conditions manipulate the high- and low-pressure baroreflex regulation of renal sympathetic nerve activity. Khan et al found that chronic suppression of the immune system with tacrolimus during high-fat diet-ameliorated hypertension and hyperfiltration. Furthermore, tacrolimus suppressed TNFα and IL-6 production, which is associated with a normalized arterial and cardiopulmonary baroreceptor regulation of renal sympathetic nerve activity.20 Another trigger of renal injury and inflammation is a chronic high salt intake. In salt-sensitive hypertension and the resulting renal injury, the endothelin pathway plays a critical role. Endothelin-1 (ET-1) is recognized by ETA and ETB receptors. Over-activation of ETA receptor is associated with hypertension and renal inflammation. De Miguel et al found that a loss of ETB receptor function contributes to high salt-induced renal injury independent of hypertension. Furthermore, the authors describe that treatment with Tauroursodeoxycholic acid (TUDCA) prevents high salt-induced renal damage associated with ETB-receptor dysfunction. De Miguel et al suggested that TUDCA may have anti-inflammatory effects by extenuating the excretion of TNFα. TNFα is an inducer of cell death and plays an important role in the development of salt-sensitive kidney disease. There is an evidence that TUDCA may be a valuable therapeutic tool for chronic cardiovascular and renal diseases, which are exacerbated by high salt diets.21 Taken together an inflammatory response is a normal reaction of the organism against inflammatory stimuli. If the inflammation gets out of control, it becomes harmful because sepsis or chronic inflammatory disease can develop. In research, there are many interesting and promising approaches to understand the pathomechanism of inflammation. Derived from this there will be more investigation relating to new treatments against inflammatory processes. The authors declare no conflict of interest.