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Understanding the NOD2 Molecular Pathway and its Epigenetics in Crohn’s Disease Pathogenesis
Lake Forest College
Lake Forest, Illinois 60045
Crohn’s Disease (CD) is an inflammatory bowel disease (IBD) that most commonly affects the small intestine. Inflammation is an immune response to a foreign body that does not belong to the organism, but sometimes the cell machinery of the organism confuses healthy cells with foreign bodies, like in CD. This inflammation thickens the intestinal walls, making it difficult to move food or stool through the intestines. An important protein involved in the pathogenesis of CD is Nucleotide Binding Oligomerization Domain 2. Several point mutations are related to CD susceptibility. Nevertheless, only about 13% of CD cases is due to genetic factors; the rest is due to environmental factors. This paper explores both the molecular and psychosomatic factors involved in CD pathogenesis. Moreover, a future study is proposed that can link the brain-gut axis to NOD2’s activation of the inflammatory response.
The refugee crisis in the Middle East and South Asia has raised a host of psychosomatic chronic illnesses due to war-related trauma. Psychosomatic illnesses are due to environmental stressors that cause a constant wear and tear on the body. For example, a population study of hypertensive individuals affected in the September 11, 2001 attacks showed increase of systolic blood pressure compared with a similar period in 2000, demonstrating the consequences of environmental stressors on hypertension (McFarlane, 2010). Healthcare professionals and geneticists will face an epigenetic crisis of chronic illnesses in refugees as political violence in their respective regions continue and their psychological trauma impose biological complications. Another chronic illness associated with environmental stressors is Crohn’s Disease (CD), a subset of Irritable Bowel Disease (IBD). CD is a chronic inflammatory bowel disease that causes one’s immune system to attack its healthy cells in the gastrointestinal (GI) tract, ensuing inflammation anywhere from the mouth to the anus. This inflammation results in symptoms such as diarrhea, ulcers, abdominal pain, and anemia. Psychosocial factors such as distress, anxiety, and depression are prevalent in IBD patients, whereby the environmental and biological factors are controlled by the brain-gut axis (Brzozowski et al, 2016). Understanding the molecular mechanisms by which genes associated with CD act upon will aid in future studies revealing how environmental stressors affect the molecular pathway of the disease. This paper shall focus on CD and the nucleotide binding oligomerization domain 2 (NOD2) gene product implicated in its pathology.
Inflammation is the general term for the body’s immune response, physically presenting as redness, swelling, and warmth. In CD, inflammation thickens the intestinal walls, making it difficult to move food or stool through the intestines. The immune system cannot differentiate between its own cells in the digestive tract or foreign bodies, causing chronic inflammation. Furthermore, this inflammation can poke holes called fistulas through the walls of the intestine, and these fistulas are prone to infection. Abscesses, anal fissures, ulcers, and malnutrition are other complications in CD (“Crohn’s Disease”, 2017).
Figure 1: Inflammation in Crohn’s Disease (“Crohn’s Disease Symptoms”, 2014).
At the molecular level, inflammation is caused by the immune system fighting against foreign bodies. The immune system can be thought of as the body’s military, a cohort of biological pathways that fight against pathogens and viruses to protect the body from disease. Like any military, the immune system is divided into several subsystems specialized in fighting specific foreign bodies. The innate immune system is a subsystem that provides immediate, short-term protection against infection from pathogens. Pathogenic microbes have established microorganism-associated molecular patterns (MAMPs) that can be detected by the host’s intracellular innate immune proteins (Philpott et al, 2014). In CD, the short-term response is dysregulated and chronic inflammation of the lining of the digestive tract occurs.
Because CD does not have a cure yet, the goal of medical treatment is management of the inflammation that causes the aforementioned symptoms. These treatments can be categorized as anti-inflammatory and immunosuppressive. Corticosteroids are a short-term medication that reduces inflammation, with the goal of achieving remission by the end of treatment. Immunosuppressants like Azathioprine and mercaptopurine are used to inhibit immune system activity to decrease inflammation but must be taken under close monitoring by the physician because they can put the patient at risk for infection (“Crohn’s Disease,” 2017). Recent studies of IBD and CD have focused on identifying the molecular mechanism by which innate immune proteins identify MAMPs. Further understanding of the molecular pathways apparent in CD may lead to another category of treatments, such as gene therapies that can fix the molecular events leading to pathogenesis. In addition, an amended understanding of the proteins and mechanisms involved can facilitate the study of drugs that repair epigenetic consequences.
Genome wide association studies are large-scale observational tests that associate loci for phenotypes using different genetic markers closely spaced across the human genome. A locus is a specific position for a gene in a chromosome. In 2010, thirty susceptibility loci for CD were identified in a GWAS. These genes have similar functions acting on the innate immune system but are located at various loci and are involved in other molecular pathways. IL10 is a gene on the first chromosome’s long arm (1q32) and was found to be associated with CD after reports that there are mutations in the IL10 receptors in early-onset CD. This gene affects cell signaling within immune cells, preventing inflammation. IL10 inhibits the synthesis of pro-inflammatory cytokines within macrophages and Th1 cells, and also suppresses antigen present cell activity. Additionally, DNA methyltransferase 3a (DNMT3A), located in the second chromosome’s short arm (2p23), was found to affect epigenetic regulation of gene transcription by methylation. In other words, these loci are involved in how environmental stressors regulate the innate immune system in CD (Franke et al, 2010). Another important locus is the nucleotide oligomerization binding protein 2 (NOD2), located in the 16th chromosome’s long arm; NOD2 was the first gene identified as a CD locus. It recognizes certain bacteria and activates genes involved in the innate immune system (Sidiq et al, 2016). Moreover, NOD2 works with other proteins in complex positive and negative feedback systems to regulate proinflammatory responses upon infection (Balasubramanian et al, 2016).
Immune cells in the lumen and mucous layer work together to maintain intestinal homeostasis. Goblet cells that form the mucous layer of the GI tract, Paneth cells that secrete antimicrobial peptides (AMP), and microbe-associated molecular pattern (MAMP) recognition systems work together to protect the gut from pathogens. In addition to regulatory immune cells, microbe-microbe interactions are also necessary to maintain intestinal homeostasis. Bacteria is often perceived as a harmful organism towards humans, but that is far from the truth. Bacteria have a significant protective function like immune cells; they secrete AMPs, use contact-dependent growth inhibition, or metabolize host carbohydrates to maintain homeostasis. Humans need bacteria in the gastrointestinal system to carry out important metabolic tasks, such as converting bile acids into secondary forms of lumen, making short-chain fatty acids involved in the inflammatory response, or combatting foreign species by secreting antimicrobial peptides. For example, increased metabolic activity in the small intestine results in hypoxia (i.e. oxygen deprivation), and this stimulates recruitment of aerobic bacteria that use the byproducts of inflammation to survive in the anaerobic environment (Ohland et al, 2014)
Infection or changes in the microbiota of the GI tract can cause a disequilibrium in the gut microbial community, also known as dysbiosis – a key feature of CD. Defective innate immune genes issue miscommunication between the intestinal microbiota and the host. For instance, an NOD2 deletion is linked with dominant and transmissible microbial dysbiosis. This microbial dysbiosis further affects the secretion of AMPs and mucin in the gut. Al Nabhani et al (2016) illustrated homogenization of gut microbiota between co-inhabiting NOD2 knockout and wild-type mice (i.e. normal mice), proving NOD2 deficiency was transmissible between organisms and causes dysbiosis. The innate immune system is made up of different immune cells that work together to trigger inflammation by producing cytokines, chemokines, and antimicrobial agents that result in phagocytosis of target cells. Interestingly, dendritic cells (DCs) can initiate T cell activation, converting an initial innate immune response into an adaptive response for long-term immunity to changes in the gut microbiota. According to Zhou et al (2017), these activated T cells promote chronic inflammation in CD. Various genes and environmental factors are involved in CD pathogenesis.
Any part of the digestive tract can be affected by CD; however, the terminal ileum of the small intestine is most commonly affected. The terminal ileum contains four layers of tissues surround the lumen (i.e. the cavity of the small intestine): the mucosa, submucosa, muscularis, and serosa. The mucosa layer is important in CD pathology; it has epithelial cells that absorb nutrients into the lumen, but before nutrients can be absorbed, they must go through lymphatic patches that detect pathogens before nutrients are absorbed into the lumen. The mucosa layer is largely composed of mucin proteins that provide the first line of defense in case the barrier between host epithelium and microbiota is compromised; NOD2-deficient mice were characterized by reduced Muc2 expression in Goblet cells; the mice’s mucosa layer was deficient in mucin proteins (Balasubramanian et al, 2016). In addition to Goblet cells, other epithelial cells in the mucosa layer include enterocytes and Paneth cells. Enterocytes absorb nutrients into the lumen, while Paneth cells secrete AMPs when faced with a pathogen. Paneth cells are of special importance in CD because they express high concentration of NOD2, the evidentiary protein affected in CD. Paneth cells are located at the base of intestinal crypts in the small intestine. The intestinal crypts contain stem cells that replenish the epithelial lining of the small intestine’s villi, which increases surface area of the small intestine so it can increase its rate of absorption. Paneth cells participate in cell signaling to protect the nearby stem cells; they also secrete defensin proteins to protect the intestinal epithelial barrier from infection (Balasubramanian et al, 2016).
Ogura et al developed a monoclonal antibody specific for human NOD2 to determine if Paneth cells expressed NOD2. They found terminal ileum crypts are rich with Paneth cells and express NOD2 twenty times more than colonic crypts that contain few Paneth cells; furthermore, NOD2 was concentrated in the cytosol nearby granules containing antimicrobial peptides (2003). This demonstrates how NOD2 dysfunction leads to increased inflammation and worse IBD pathology in the small intestine than other organs in the gastrointestinal tract.
Figure 2: Inflamed terminal ileum of a CD patient shows expression of NOD2 in Paneth cells at the base of the intestinal crypt; see arrows (Ogura, 2003).
As mentioned earlier, psychosocial stress is implicated in CD pathogenesis; this is due to changes in the brain-gut axis. This stress-response system is composed of the hypothalamic pituitary adrenal (HPA) axis and autonomic nervous system (ANS). According to Brzozowski et al (2015), the brain-gut axis regulates appetite, autonomic nerves, enteric nervous system, sensory neurons, motor neurons, neurotransmitters, and endocrine pathways. The HPA axis is a hormonal response system that releases stress hormones that interact with the adrenal cortex to release cortisol; cortisol is a steroid hormone that releases sugars for the body to use in its response to stress and regulate the inflammatory response. The ANS moderates the body’s involuntary response mechanisms and releases adrenaline in response to stress so the body responds faster to stimuli. Chronic stress puts the body in a constant over-working state to keep its biological systems ready to fight. Stress-induced modifications of the ANS and HPA axis include the release inflammatory cytokines, short chain fatty acids (SCFA), and microbial products into the lumen of the GI tract. In summary, chronic stress can lead to chronic inflammation.
Furthermore, glucocorticoids are a class of steroid hormones in the immune system involved in the inhibition of inflammatory responses. They interact with transcription factors by binding to their respective glucocorticoid receptor on the plasma membrane of a cell and turning on a signaling cascade. Post-traumatic stress disorder (PTSD) studies have demonstrated suppression of the HPA axis due to stress because of increased glucocorticoid receptors in lymphocytes and suppression of cortisol (Maunder et al, 2000). Lymphocytes are white blood cells involved in the immune system. Heat shock proteins (Hsp) are another class of proteins that are upregulated under stressful cellular conditions such as elevated temperature, toxins, or oxidants. They bind to denatured proteins and help them refold into their native fold. The epithelial cells of the lumen produce HSPs in response to an environmental stress, and the HSPs form a complex with glucocorticoid receptors to enhance the inflammatory response. Chronic stress upregulates HSP activity and glucocorticoids, which leads to the inflammation seen in CD. Still, the extent to which HSP-Glucocorticoid Receptor complexes are efficient under constant activation is not well understood (Maunder et al, 2000).
According to Zhou et al (2017), genetic factors explain only 13.1% of CD variation;
epigenetic factors, such as stress-induced modifications of the brain-gut axis, may have a more significant role in CD pathogenesis, acting as “mediators of the genome”. Considering the aforementioned biological and environmental components involved in CD pathology will assist in understanding the cardinal gene involved in these processes: nucleotide binding oligomerization binding protein 2 (NOD2). How does NOD2 function and what is its relationship with the brain-gut axis?
Molecular Function of NOD2
As mentioned previously, pathogens have conserved microorganism-associated molecular patterns (MAMPs) that can be detected by the host’s intracellular innate immune proteins, such as NOD2. NOD2 is a cytosolic protein that responds to intracellular fragments of bacterial peptidoglycan. Peptidoglycan is a polymer found in the cell wall of bacteria composed of N-acetylglucosamine and N-acetylmuramic acid (muramyl dipeptide) chains held together by short peptide bonds. Upon infection, the pathogen’s peptidoglycan surface is recognized by epithelial cell membrane proteins in the mucosa layer and is taken into the cytosol by endocytosis. NOD2 recognizes muramyl dipeptide (MDP) peptide fragments of the polymer, and then initiates transcription of nuclear factor‑κB (NF‑κB) to elicit an inflammatory response that leads to pro-inflammatory immune factors, such as recruiting macrophages to phagocytose, or “eat”, the pathogen (Philpott et al, 2014).
NOD2 is comprised of three domains: C-terminus leucine-rich repeat (LRR) region, central nucleotide-binding domain (NBD), and N-terminus tandem caspase recruitment domains (CARD). The LRR domain is involved in ligand sensing and recognition of MDP to trigger a conformational change in the proteins. The tandem CARDs dimerize MDP and NOD2, which promotes NBD-mediated oligomerization of NOD2. NOD2 oligomerization promotes the recruitment of the downstream receptor-interacting protein kinase 2 (RIP2), which activates the NF‑κB. In addition, NOD2 interacts with and is stabilized by the molecular chaperone Hsp70. Schaefer et al (2017) demonstrated how even the protein products of critical NOD2 mutations implicit in CD can be rescued by Hsp70; CD can be characterized as a protein misfolding disease.
Several other downstream proteins are involved, RIP2 recruits TRAF6, a signal transducer, and TAK1, a kinase, to ubiquitinate NEMO. NEMO is a NF-κB modulator made up of IκB-α and IκB-B, which forms a complex with TAK1 to activate IκBα kinase to initiate the NF-κB signaling pathway. IκB-α gets phosphorylated and is targeted to proteasomal degradation that permits free NF-κB to translocate into the nucleus and transcribe anti-inflammatory proteins like cytokines (Sidiq et al, 2016).
Since NOD2 causes the recruitment of TAK1, it is also involved in the MAPK activation; MAPK directs proinflammatory cytokines to the area of stimuli (i.e. infection). Moreover, NOD2 recruits ATG16L1, an autophagy protein, at the plasma membrane that directs lysosomal degradation of the pathogen; this process is irrespective of downstream signaling leading to NF‑κB activation. In other words, NOD2 can evoke autophagy of the pathogen at its point of entry.
Figure 3. NOD2 molecular pathway (Sidiq et al, 2016).
Many loss-of-function polymorphisms in NOD2 are related to MDP sensing; for example, homozygosity in the 3020InsC frameshift variant of NOD2 produces a gene product unable to locate the plasma membrane and self-oligomerize to activate the NF‑κB signaling cascade. Additionally, CD susceptibility can also be explicated by variation in the autophagy genes ATG16L1 and immunity-related GTPase family M (IRGM).
Several studies have illustrated the molecular function of NOD2, and how it interacts with other proteins to activate the NF‑κB transcription factor. These mice/model organism studies have been monumental in identifying the function of NOD2 and the key proteins involved in its NF-κB signaling pathway. For example, Barnich et al (2005) found that GRIM-19, a protein with homology to the NADPH dehydrogenase complex, interacts with endogenous NOD2 in human colon (HT29) cells. It is required for NF-kB activation following NOD2-mediated recognition of bacterial MDP and controls pathogen invasion of intestinal epithelial cells. The study performed yeast two-hybrid screening and identified GRIM-19 as an interacting protein with NOD2 in mammalian cells. GRIM-19 is located on chromosome 19 and induces cell death. The study showed cytoplasmic localization of GRIM-19 and NOD2. Salmonella infection increases grim-19 mRNA in infected Caco-2 yeast cells.
Lessard et al (2017) found that the modulation of Ly6C(high) monocyte phenotype and function can be induced by the NOD2 receptor. Monocytes are a type of blood leukocytes that regulate inflammation by expressing NOD2. There are two kinds of monocytes: inflammatory monocytes like Ly6C(high) that respond to local inflammation and patrolling monocytes like Ly6C(low) that are prominent in the vasculature of the tissue and act transiently. MDP was used to trigger NOD2 in this study that used Nr4a1-I- mice that lacked Ly6C(low) monocytes; Lessard et al. studied monocyte plasticity by stimulation of NOD2 receptor with MDP. They found that MDP treatment promotes the conversion of inflammatory Ly6C(high) monocytes into a Ly6C(low) patrolling subset, MDP treatment increases levels of Ly6C(low) monocytes and reduces inflammation in liposaccharide-treated (induces acute inflammation) mice, and MDP treatment induced strong activation of the IL-6 gene, gene associated with anti-inflammatory properties, in Ly6C(high) and Ly6C(low) monocytes.
Hemisaat et al (2017) found that NOD2 signaling is required for the innate and adaptive intestinal and systemic immune responses upon C.jejuni infection of secondary abiotic IL-10-/- mice but does not limit pathogenic infection. Secondary abiotic IL-10-/- mice were infected with intestinal microbiota to start a pathogen-induced enterocolitis that could model a human C. jejuni-host infection. NOD2-deficient IL-10−/− (Nod2−/− IL-10−/−) mice and IL-10−/− counterparts both were standardized to have depleted intestinal microbiota to warrant pathogen-induced enterocolitis. They found that Mucin-2 mRNA expression was dependent on NOD2 expression and was upregulated upon expression to maintain the mucus membrane integrity. With the NOD2−/− knockout mice, the expression of Mucin-2 mRNA was downregulated.
Experiment for the Future
(Schaefer et al, 2017)
An interesting avenue of research is the function of Heat Shock Protein (Hsp)-Glucocorticoid Receptor (GR) complexes in the NOD2-NFkB pathway. As mentioned earlier, chronic stress upregulates HSP activity and glucocorticoid activity, which leads to inflammation in CD. Moreover, Shaefer et al (2017) demonstrated how Hsp proteins rescue NOD2 function even with CD-implicated mutations by helping the protein fold correctly. Similar to how Hemisaat et al (2017) evaluated the role of NOD2 in C. jejuni infection with knockout mice, a similar method will be employed comparing NOD2−/− knockout mice and their counterparts to determine its role in the Hsp-Glucocorticoid Receptor complex activity in the brain-gut axis. We expect downregulation of Hsp-GR expression when the expression of NOD2 is turned off, resulting in increased ilea inflammation in knockout mice.
How Hsp70 and GR are expressed in the absence of NOD2 with the presence of adverse stimuli will illustrate the impact of the brain gut access in inflammatory response. NOD2 knockout mice and wild-type mice will live in cages, and they will be faced with an adverse stimulus every day over the course of 5 weeks. The expression of Hsp70 and GR will be measured in both, illustrating a pro-inflammatory response to the adverse stimuli. The control mice will have their NOD2, and its expression will be measured as well to compare differences in inflammatory response because of NOD2.
Generation of secondary abiotic mice
Female IL-10 and male IL-10 mice lacking NOD2, the same used in the Hemisaat et al (2017) study are bred and kept in a pathogen-free environment for three weeks. These mice can be ordered from Cyagen Biosciences, a transgenic mice manufacturer. The mice are injected with various antibiotics for 8 weeks to counteract colonization resistance and assure stable intestinal colonization of microbiota. They are given ampicillin plus sulbactam (1 g/L), vancomycin (500 mg/L), ciprofloxacin (200 mg/L), imipenem (250 mg/L), and metronidazole (1 g/L) to autoclaved drinking water. As a control, all food and water given to these mice throughout the study is autoclaved. Three days prior to undergoing an adverse, stressful event, this “antibiotic cocktail” is replaced with water.
Adverse Environmental Experiment Conditions
The control and knockout mice will stay in their respective, pathogen-free, cage with other mice. In each cage there will be one mouse hit by a wooden ball once a day, and the mice will be chosen at random every day over the course of 5 weeks. Not only will mice be stressed from getting hit by a wooden ball, they will be stressed by the apprehension of being hit by a wooden ball. This is similar to human environmental conditions of refugees living in their respective countries facing political violence every day.
RNA was isolated from Paneth cells in frozen terminal ileum biopsies, reverse transcribed, and analyzed. The expression of Hsp70, GR, and NOD2 (wild-type mice) in NOD2 knockout and NOD2 wild-type mice was analyzed using Light Cycler Data Analysis Software. Following the control model used by Hemisaat et al (2017), the mRNA of the housekeeping gene for hypoxanthine-phosphoribosyl transferase (HPRT) was used as a reference, and the mRNA expression levels of the individual genes were normalized to the lowest measured value and understood in arbitrary units (Hemisaat et al, 2017).
This experiment will shed light on any dependency of the brain-gut access on NOD2. This can implicate an epigenetic cause for upregulation of the NOD2 mediated NFkB pathway. Some issues that may occur is that different types of stress may yield different responses for different stressors; it is hard to standardize the stress-response between model organisms. Moreover, we expect down regulation of Hsp and GR proteins, which will be shown by the Real-time PCR. However, there are several other proteins between NOD2 and NFkB that may cause downregulation of Hsp and GR; for example, TAK1 is involved in MAPK activation implicit in pro-inflammatory cytokine production, which can have homology with the Hsp-GR complex’s role in promoting the inflammatory response. There are unfortunately not enough studies regarding the Hsp-GR complex to understand which pro-inflammatory signaling pathway it is involved in. A future study could possibly consider knocking out receptor molecules/intermediates like NOD2 and TAK1 and comparing their inflammatory response. Lastly, another issue is that mice may have different forms of dysbiosis and there is potential of them infecting each other in the pathogen-free cage; this goes for both the control and knockout mice. Nabhani et al (2016) demonstrated cohabitations can cause homogenization of mice’s microbiota dysbiosis.
In conclusion, the NOD2 protein has a significant molecular role in CD. However, there are several environmental factors that lead to its pathogenesis, and they should be studied more closely now that there is a better grasp of the protein’s mechanism in inciting the inflammatory response. Understanding how neuroendocrine mechanisms affect the #1 susceptibility loci of CD will aid in decreasing the ever-increasing prevalence of psychosomatic diseases in populations who have experienced significant amounts of psychological trauma. An inflammatory response is important to protect our bodies from disease, but only when there is something to fight our bodies should respond. NOD2 has multiple pathways of inciting the inflammatory response and learning more about its other pathways outside the gut will significantly add to our understanding of CD.
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