Inflammation and its Disease Consequences

    

    

    Figure 1: Disease Conditions resulting from Inflammation.
    

The net effect of the expression of pro-inflammatory mediators culminates in the local signs of inflammation including swelling, redness, pain, and loss of function. In most cases, this is followed by the resolution of inflammatory response, where the cells hosting the inflammatory event revert back to a non-inflammatory phenotype. This phase starts soon after the granulocytes signal a termination sequence and promote the switch of arachidonic acid–derived prostaglandins and leukotrienes to lipoxins and the recruitment of neutrophil followed by their apoptosis by resolvins and protectins [19]. Consequently, macrophages phagocytose these apoptotic neutrophils leading to neutrophil clearance and cellular debris. Further the release of anti-inflammatory and reparative cytokines such as transforming growth factor- β1 mark the end along with the clearance of macrophages through the lymphatics [20]. However, when this acute phase of inflammation does not meet it usual end, then the actual complications arise leading to the development of chronic inflammation. It is this chronic inflammation which triggers the development of many diseases discussed in the review, Figure 1. The current review highlights the mechanism of inflammation in general as discussed above and further diverges into its various disease implications.

Inflammation in cancer

The discussion of the link between inflammation and cancer could not start without mentioning the pioneer hypothesis given by German pathologist Rudolf Virchow in 1863 [21]. He detected inflammatory infiltrates in solid malignancies and concluded that cancers are more prone to occur at sites of chronic inflammation. After this pioneering observation and much research, it is now a wellestablished fact that inflammation plays a critical role in promoting cancer. An inflammatory microenvironment forms the niche for all tumors [22,23]. Improper resolution of inflammation and an unchecked inflammatory reaction can induce chronic inflammation, predisposing the host to cancerous consequences [24]. This all happens with a random growth of a tiny tumour which starts growing from a few cells and scavenges enough oxygen and nutrients from its surroundings. As it grows further, macrophages and granulocytes infiltrate the tumour, where they release cytokines which further initiate the growth of blood vessels or angiogenesis.

Studies show that the inflammatory microenvironments not only triggers cancer cell growth but also causes mutations in the cells by producing reactive oxygen species (ROS) and Nitric oxide Synthase (NOS)-derived nitrogen intermediates causing much DNA damage and genomic instability [25]. For instance, there is an evidence which proves that pro-inflammatory cytokines, namely TNF-α and IL-6, induce breast cancer cell growth and tumor formation, and induce adhesive recruitment of metastatic breast cancer cells [26,27]. The association between inflammation and cancer could further be observed in the case of colorectal cancer whose risk was 10-fold greater if linked with inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease [28,29]. Similarly, in the gastrointestinal tract, gastric Helicobacter pylori infection is the leading cause of adenocarcinoma and mucosa-associated lymphoid tissue lymphoma [30,31]. This is the reason why the risk of esophageal cancer, pancreatic cancer, and gallbladder cancer may be increased by inflammatory diseases, such as esophagitis, Barrett’s metaplasia, and chronic pancreatitis [31,32].

The connection between inflammation and cancer does not operate in one direction only as numerous studies showed that DNA damage can also lead to inflammation. Cancer-associated oncoproteins such as Ras, Myc and RET can also lead to inflammation by activating signaling pathways involved in the production of proinflammatory cytokines and chemokines [22]. Therefore, based on the literature, it can be concluded that inflammatory response is an integral part of cancer biology, either resulting in or beginning from tumorigenesis. In both ways; either tumor resulting from inflammation or inflammation resulting from tumor, the key players constituting the pro-inflammatory cytokine remain the same.

Inflammation in atherosclerotis

Inflammation plays a key role in the formation and progression of atherosclerotic plaques. Hence, nowadays, anti-inflammatory treatments are evaluated as novel treatments for atherosclerosis [33]. Much experimental work has elucidated the molecular and cellular pathways of inflammation that promote atherosclerosis by an inflammatory subset of monocytes/macrophages which accumulate in atherosclerotic plaque and produce pro-inflammatory cytokines.

Normally, endothelial cells (ECs), which form the innermost surface of the artery wall, resist adhesion and aggregation of leukocytes and promote fibrinolysis. However, external stimuli like hypertension, smoking, hyperglycemia, obesity or insulin resistance can initiate the expression of adhesion molecules by ECs that selectively recruit various classes of leukocytes to the arterial wall [34]. Hence, the normal homeostatic functions of these adhesion molecules are disturbed which then make their way into the intima. Although, it is the property of the endothelial monolayer to resist this leucocyte adhesion coming from the flowing blood, however there are helpers which aid this process. The first of these include the vascular cell adhesion molecule-1 (VCAM-1) which helps in the attachment of leucocytes to the arterial wall or intima [35]. Further, after a high atherogenic diet the modified lipoprotein particles including the oxidized phospholipids and fatty acids induce the pro-inflammatory cytokines such as interleukin (IL)-1b or tumour-necrosis factor-α (TNF-α) which eventually activate nuclear factor-kB (NF-kB) for the transcriptional activation of the VCAM-1 gene, thus further aiding the leucocyte adhesion [36]. It could also be noted that the oxidized LDL which assist in this process arose from the modulation by nitric oxide (NO) and other products resulting from the neuronal nitric oxide synthase (nNOS) [37,38]. Once recruited, the leukocytes make their way to the intima by diapedesis between endothelial cells at their junctions. Factors like monocyte chemoattractant protein-1 (MCP-1) and IL-8 play important roles as a leukocyte chemoattractant during atherogenesis [39]. The resulting Atheroma further overexpresses the chemokines that may contribute to more lymphocyte recruitment. These leucocytes further undergo maturation to become macrophages after going through a series of morphological changes. This marks the appearance of what we call the “foam cell formation”, a hallmark of atherosclerosis [40]. These macrophages which constitute the foam cells continue to release various growth factors and cytokines (eg, platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-), macrophage-colony stimulating factor (M-CSF), involved in lesion progression and complication. All these events further accelerate the replication of macrophages within the intima. It has been identified that most of the macrophage related activities including its maturation from monocyte to the lipid-laden macrophage, migration and proliferation could be attributed to M-CSF [41]. This could be directly reflected in animal experiments where mice lacking M-CSF show retarded lesion development with markedly reduced macrophage accumulation [42,43]. Further, the lipid-enriched fatty streak developed from the macrophages along the vessel wall evolve into complicated atheroma through multiplication of smooth muscle cells which accumulate in the plaque and lay down an abundant extracellular matrix. This eventually narrows down the arterial lumen and further hampers the coronary circulation leading to clinical complications like angina pectoris, acute myocardial infarction etc [44].

The pivotal role played by inflammation is crucial to the pathogenesis of atherosclerosis. The multiple oxidation events in chronic inflammation form the basis of the complications associated with inflammation driven atheroschelorsis.

Inflammation in diabetes

The close link between metabolism and immunity is unquestionable. It has been evident from many studies that chronic inflammation is associated with obesity linked diabetes [45]. The molecular and cellular signaling pathways leading to obesity-induced inflammation enormously contribute to diabetes. The interesting observation by the scientists on the connection of metabolic syndrome and activation of the immune response provided direct clues of a link between diabetes and inflammation. Many clinical events take place leading to the onset of Diabetes. Mechanisms including glucotoxicity, lipotoxicity, oxidative stress, endoplasmic reticulum (ER) stress, alterations of the gut microbiota, endocannabinoids and the formation of amyloid deposits in the islets etc are all associated with inflammatory responses [46-48]. The association between Diabetes and inflammation though straightforward, has still many missing links. However, with data published so far, many theories linking inflammation-driven mechanisms to diabetes could be understood in detail. One among those is the obesity linked factor where there is a subsequent polarization of Macrophages to the ‘‘classically activated macrophages’’ phenotype, M1 which secrete pro-inflammatory cytokines such as IL-1b, IL-6, TNF-a, from the ‘‘alternatively activated macrophages’’ phenotype, M2 which produce anti-inflammatory cytokines such as IL-10 [49]. Obesity not only leads to adipose tissue macrophages infiltration, but also causes a phenotypic switch from the anti-inflammatory M2 to pro-inflammatory M1 phenotype. The downstream signaling from these M1 macrophages impairs insulin signaling [50]. Another widely accepted theory emphasizing the idea that it could be other way round, with the increase in the level of glucose triggers inflammation which subsequently prompts for diabetes [51]. This happens in pancreatic islets where elevated glucose concentrations increase the metabolic activity of islet cells, leading to elevated formation of reactive oxygen species (ROS). ROS promotes activation of the NLRP3 inflammasome and release of IL-1β [52]. Other factors leading to increased production of IL-1β, include ER stress due to increased insulin demand and production, lipopolysaccharides from bacterial cell walls (endotoxins) or free fatty acids bound to Fetuin A and thus activating NF-κB via TLR2 or TLR-4 [53,54]. IL-1β further induces IL-6, IL-8, tumour necrosis factor (TNF) and monocyte chemoattractant protein 1 (MCP1) which consequently attract macrophages and other immune cells. In macrophages, the high accumulation of glucose and lipids promote the formation of inflammasomes that lead to the splicing of pro-IL- 1β to active IL-1β [55,56], which further carry forward the signaling by attracting multiple immune cells thereby promoting insulin resistance.

Inflammation in neurodegenerative diseases

The adult human central nervous system (CNS) consists of billions of neurons and glia cells, namely microglia [57]. Microglia is basically macrophages present in the brain and spinal cord and form the frontline defense mechanism of its innate immune system. Under physiological conditions the resting microglia displays a deactivated phenotype and surveys the microenvironment and produce factors that influence surrounding astrocytes and neurons. However, any disturbance in the CNS environment caused by alterations formed by pathogen invasion or tissue damage, results in microglia and astrocyte activation. This activated phenotype of microglia promotes an inflammatory response that serves to initiate the tissue repair by producing and releasing neurotrophic factors or cytokines. However, in case of prolonged neuronal damage, they release pro-inflammatory cytokines by astrocytes and microglia which further leads to an enhanced local inflammatory reaction. The activated microglia and astrocytes can produce ROS along with the pro-inflammatory cytokines which further contribute to neurodegeneration process due to its high reactive ability [58-60]. This forms the basis of several neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Infact the presence of pro-inflammatory cytokines and activated immune cells, is an important feature of all neurodegenerative diseases [61,62,63]. Since, there is clear indication of the presence of a common link between various neurodegenerative diseases and activation of innate immune responses, the role of inflammation could be easily understandable. This could be understood in more detail by individually looking into few of the important neurodenerative diseases.

Alzheimer disease: AD is one of the most common causes of dementia in the elderly people. Clinically, it is characterized by loss of memory, cognitive impairment and various neuropsychiatric disorders including behavioral and neuropsychiatric disturbances [64]. The typical neuropathological feature in AD is the accumulation of extracellular β-amyloid plaques (Aβ) composed of aggregated, cleaved products of the amyloid precursor protein (APP) and intracellular neurofibrillary tangles (NFTs). This is also formulated mainly by comprising the hyper phosphorylated forms of microtubule-binding protein tau. These aggregates of Aβ have been shown to activate microglia which successively induce the production of inflammatory factors like nitric oxide (NO), ROS as well as proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), and chemokines (e.g., IL-18) [65]. Other studies also suggest that Aβ fibrils trigger inflammatory responses through TLR4/TLR6 in the presence of CD36 [66].

Parkinson disease: PD is a chronic progressive neurodegenerative disease, which is clinically characterized by motor symptoms (bradykinesia, tremor, rigidity, and postural instability) and nonmotor- related symptoms (olfactory deficits, autonomic dysfunction, depression, cognitive deficits, and sleep disorders) [67,68]. PD is also due to abnormal accumulation and aggregation of misfolded α-synuclein. There are reports clearly indicating the direct role of α-synuclein in increased ROS production which results in oxidative damage, mitochondrial dysfunction, and ultimately cell death, thus creating a vicious cycle promoting neurodegeneration [69-72]. Microglia activation is the key to neurodegeneration of neurons in the substantia nigra (SN). Various in vivo studies have demonstrated that the serum and cerebrospinal fluid of PD patients have higher levels of IL-1β, TNF-α, and IL-2 and also CD4+ and CD8+ T lymphocytes.

Studies have also revealed that PD patients show elevated serum levels of TNF-α and TNF-α receptor 1 as compared to control subjects. This could contribute to PD pathogenesis [73-75]. Many proinflammatory cytokines including IL-1β, TNF-α, and IL-6, have also been described in SN of postmortem tissue of patients [68].

Multiple sclerosis: Multiple sclerosis (MS) is a heterogeneous and complex autoimmune disease of the central nervous system (CNS) due to autoimmune aggression against myelin and neuronal antigens [76]. It was noticed in the earliest studies on multiple sclerosis pathology [77] that axonal injury and loss occur in the disease lesions and their extent correlates with the degree of inflammation. The major characteristic of MS lesions is infiltration of lymphocytes and antibody-producing plasma cells into the perivascular region of the brain and spinal cord white matter. This is aggravated by an increase in activated microglia and demyelination [78].

Inflammation in rheumatoid arthritis (RA)

RA is a progressive, inflammatory autoimmune disease characterized by chronic, symmetric and erosive synovitis occurred mainly in peripheral joints [79]. Many inflammatory pathways including Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT), the stress-activated protein kinase/mitogen-activated protein kinase (SAPK/MAPK) and Phosphatidylinositide-3-Kinase/AKT/mammalian Target of Rapamycin (PI-3K/AKT/mTOR) pathways have been shown to be involved in RA [80-84]. As discussed previously, pro-inflammatory cytokines like TNF and IL-1 are a key component in the process of chronic joint inflammation and the concomitant erosive changes in cartilage and bone. As a matter of fact, TNF-α and several of the interleukins (IL) including, IL-1, -6, -7, -8, -12/23, -15, -17, -18, -32, -35 and proteins of the interferon (INF) family were found to be elevated in RA sera [85]. In fact excess levels of IL-6 are produced in people with RA, specifically in the tissue layer covering the joint. There are clear reports of the role of deregulated activation of JAK/ STAT pathway along with its cross-talk with SAPK/MAPK, PI-3K/ AKT/mTOR pathways [80-84] in rheumatoid arthritis. Also, spleen tyrosine kinase (Syk) [86], the sphingosine kinases, SphK1 and SphK2, transforming growth factor β-activated kinase-1 (TAK1) [87], bone marrow kinase (BMX) [88] and nuclear factor-κBinducing kinase (NIK) [89] are involved in the onset and progression of RA. Also, direct evidence shows the role of BMX in p38 kinase and JNK phosphorylation as well in the activation of NF-κB [89]. Hence, BMX may be responsible for regulating the activation of p38, JNK and NF-κB, all of which are critical to the inflammatory response cell survival and apoptosis. The proinflammatory cytokines and growth factors activate the STAT proteins in the JAK/ STAT pathway, while the increase in neutrophil, macrophage and eosinophil chemotaxis and activation of T- and B-cells resulted in Tumor Necrosis-Related Apoptosis-Inducing Ligand (TRAIL) and IL-15 induced activation of PI-3K/AKT/mTOR pathway. All these factors clearly indicate the important role played by inflammatory signaling in the onset and progression of Rheumatoid Arthritis.

Conclusion

This review provides key links between the inflammatory signaling pathways and various diseases. Inflammation appears to play a critical role in many chronic diseases. Inflammation as a first defense mechanism of the body is helpful in combating incoming pathogens inside the body. It is this primary acute inflammation which protects and heals the body after an injury or infection which is essential and normal. However, when the acute phase is prolonged by excess or consistent stimuli, it results in becoming chronic which deteriorates the situation in many diseases.

Many diseases discussed above have either been a result of the inflammatory pathway already going on at the site of action or the disease itself triggers an inflammatory response which further aggravates the situation. However, in almost all cases inflammatory cells and cytokines take the lead in further progression of the disease. From past many years, investigators have understood the signaling mechanisms linking inflammation to diseases. Hence, reaching the root cause of the disease has become much easier, considering that most of these have an inflammatory angle to it. Through this review, we tried to focus on various diseases derived directly or indirectly by inflammatory pathways and how a careful observation in each of these would bring in important targets for therapeutic intervention.

Acknowledgments

This work was supported by the Science & Engineering Research Board (SERB) Young Scientists Start-Up Research Grant under grant number YSS/2015/001279 to U.S, Department of Biotechnology sponsored DBT-Ramalingaswami fellowship and CSIR-EMR-II funding to MSB. The authors also gratefully acknowledge the facilities provided by the Indian Institute of Technology Indore, for providing facilities and other support.

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