Inflammation is a message

Inflammation is a vague concept. Most people are familiar with this word and use it in their daily conversations.  Itchiness, rashes or some pains. For healthy individuals, inflammation should be temporal and spatially restricted. In patients with autoinflammatory diseases, such as atopic dermatitis (eczema) and Crohn's disease, and in individuals experiencing allergic reactions, inflammation is prolonged, occurs in multiple locations, and is hyperreactive. 

In these statements, inflammation sounds like a bad thing to be suppressed. I wonder if anyone has ever used the word “inflammation” in a good context?  Then, why does such a bad thing occur in our bodies?

Inflammation is not something you can intentionally initiate. It happens. But when it happens, there must be a reason—the cause of the inflammation. This cause must be physical materials, not imagination.

Inflammation manifests as itchiness, rashes, or pain. The cause is physical materials, such as surface sugars of viruses or bacteria, which are not components of eukaryotic cells, and leaked intracellular materials that should not be present in the extracellular space. The presence of physical materials that should not be present in the extracellular space triggers the inflammatory reactions. Although these physical materials are the triggers, they are not the inflammation itself.

Then, their presence needs to be recognized by someone in some way. Without recognition, no subsequent events. This first step of recognition is known as innate immunity. The physical materials are recognized by protein receptors, which can directly bind them. This triggers the activation of intracellular signalling cascades, leading to the release of cytokines and chemokines. This happens within individual cells.

In analogy, you witness a car accident. You make a 911 phone call. You recognize the accident, then take action. If no witness, an accident is not recognized. Many witnesses, many phone calls. The phone call is equivalent to the first step in triggering inflammation, not the accident itself.

What happens next? Emergency vehicles and police cars. Wrecker trucks. Rubberneckers, too. The road is blocked, creating long traffic jams.

In the event of a single-car accident, the road is quickly cleared and the jams are resolved, returning to normal. In the event of a significant accident, firefighters and police officers request additional support. The wider area might be completely locked up.

This may take days to recover to normal fully. The phone call is the internal trigger to recruit professional help from far away. When the original trigger is cleared (i.e., a car accident), which is always a physical event, no one makes a phone call anymore.

The same thing happens in our bodies. Physical materials originating from viruses, bacteria, or cellular damage are recognized by tissue-resident macrophages (TRMs). TRMs recognize and phagocytose them. The physical materials will be sequestrated inside the TRM and digested.

TRMs also serve as witnesses to make a phone call – secreting cytokines and chemokines to recruit immune cells circulating in blood vessels. The secretion of inflammatory cytokines closes the lymphatic drainage, preventing pathogens from spreading elsewhere. The local edema is due to increased fluid leakage from capillaries, along with drainage system closure, similar to a road closure in a car accident.

What I want to highlight here is that a phone call is made by a person who witnesses an accident—a private event. Similarly, the secretion of inflammatory cytokines is made by a cell that recognizes physical materials associated with pathogens and damage. Not sporadic or imaginative events. But private physical interaction results in cognition within individual cells. Therefore, when the physical interaction is cleared, inflammation will cease.

Chronic inflammation occurs when physical materials from pathogens or cellular damage are not fully cleared. Autoimmune disorders involve hyper- or mis-sensitivity to non-car accidents. For example, making a phone call when one sees a white car or McDonald’s. There should still be a causative physical material that initiates a phone call, inflammation.  In case of an allergy, the causative material is abundant in the environment, making it almost impossible to be cleared. Thus, the inflammation sustains. This means that the constant presence of emergency vehicles, police cars, wrecker trucks and rubberneckers on the road.

By this point, I hope you recognize the importance of physical interactions between pathogen/damage-derived materials and their specific recognition receptors. This interaction is similar to how our senses work. The eye’s photoreceptors sense different wavelengths of light through physical interactions of photons and rhodopsin. Olfactory receptors detect smells by physical interactions between chemicals (physical materials) and their receptors. Simultaneously, the photoreceptor cannot smell, and the olfactory receptor cannot see. This is also true in the recognition of pathogens/damage. Each recognition (i.e. stimulus/receptor relationship) is specific and unique.

Most recognitions occur on the cell surface. Extracellular stimuli (i.e., physical materials) bind to their cell-surface receptors. Interestingly, some recognition occurs in the cytoplasm.

Viruses have no metabolism of their own. They infect eukaryotic cells to amply their genetic materials using host metabolism. Their genetic materials are DNA or RNA. Virus infection is the deposition of its DNA or RNA into a cell. Its genetic material is amplified, and packaging proteins are produced by the host’s translational machinery. 

Are there any defence mechanisms against viral infection in eukaryotic cells? For defending against viral infection, an eukaryotic cell needs to recognize viral DNA or RNA and distinguish it from its own. They are the same materials, just with sequence differences. How are they identified?

First, the cell’s own self DNA is sequestrated into the nucleus or mitochondria, which are membrane-separated compartments in a cell. Therefore, cytosolic DNA can be considered a viral infection.

Second, the cell’s own RNA has specific chemical modifications, pseudouridine. tRNAs, mRNAs and rRNAs are chemically modified. RNAs lacking the modification are recognized as viral. dsRNAs do not exist in eukaryotic cells; they are produced by retroviral infection.

Therefore, viral infections can be recognized based on the presence of cytosolic DNA and the chemical properties of RNA. After the recognition by individual sensors, the type 1 IFN response is activated to initiate inflammation in an individual cell.

Since viral DNA and RNA are intracellular materials, phagocytosis by macrophages is ineffective. One way to remove them is with cytosolic exonucleases. Then, inflammation will cease. The second way is that the cell should be killed by a T-cell.  Elimination of an inflammatory cell – i.e. killing a phone caller. When a virus infects a cell, it takes over its translational machinery. In my analogy, it takes over the closet. Your outfit (i.e. clothes) will change drastically in addition to making a phone call. This change will be recognized by T-cells, which will then kill it.

Inflammation never happens automatically but must have a physical cause: physical materials. The physical materials need to be recognized and responded to in individual cells. When physical materials are cleared (digested or sequestered), inflammation will cease.

There are two steps of phone calls. The phone calls by witnesses of an accident and the second steps by firefighters and police men asking for further support. In pathogen infections and cellular damage, tissue-resident macrophages (TRMs) are the first witnesses and the fire extinguishers. They can clear them up or make a support call. For viral infection, the first witness is the infected cell itself, usually an epithelial cell. The cell has a chance to die through a process known as apoptosis. If not, TRMs recognize the phone call, inflammation. Then, amplify it to recruit the circulating immune populations (the second call). If the infected cells are apparently different — like a distinct outfit from the usual — the cells will be killed by T cells.

Cancer is a very interesting disease. Without pathogens and cell damage, inflammation occurs. I keep mentioning that the initiation of inflammation is absolutely dependent on physical material stimulation activating its receptor in a cell. In cancer, what is sensed and who is making the phone call?

In eukaryotic cells, DNA should be in the nucleus or mitochondria. No other place except during mitosis. During mitosis, the nuclear membrane is broken down, and the chromosomes, which are compacted DNA, are transiently exposed to the cytoplasm. That is the only transient phase in the cell cycle; DNA is permitted in the cytoplasm.

During chromosomal segregation of mitosis, all 46 chromosomes synchronously move together from the metaphase plate at the center of the mitotic spindle to the opposite poles to form the two daughter nuclei. Chromosomes have the ability to create a nuclear membrane. When all chromosomes move together, one nucleus with one large connected membrane. However, if any chromosome delays joining with others, it can form its own nuclear membrane. This small nucleus is called a micronucleus. Sometimes it fuses with the main nucleus quickly. However, when it stays, problems arise. In this small nucleus, not enough materials to support transcription and replication. The membrane curvature is too high due to a small radius, making it prone to rupture. Replication is stalled but not easily restored. Rapture exposes DNA to the cytoplasm. As I mentioned, cytosolic DNA is considered a viral infection.

The integrity of the DNA sequence is vulnerable during DNA replication. This vulnerable process should not be perturbed, because once errors in the sequence are introduced, they will be passed on to their progeny. If there aren't enough dNTPs, what will happen? If not enough replication proteins for origin firing or polymerization? Replication folks will be stalled. Imagine you are cooking your favourite dish and realize that some ingredient is missing or your stove is not working. Better to know in advance. If you knew, you wouldn't have started.

This is the same for the cell. A shortage or malfunction of something during a series of sequential events is highly problematic, costly to restore the original process and error-prone.  One known problem related to stalled DNA fork progression is the formation of a DNA-RNA complex (R-loop), which is more stable than a DNA-DNA double helix. To resolve this, the section of the R-loop complex needs to be excised using the homologous recombination DNA repair pathway. The excised R-loops are released to the cytoplasm. However, again, they are recognized as a viral infection. 

In our genome, numerous DNA sequences originated from viruses, known as retroviral elements. They cannot produce infectious virus anymore because there is no sequence for the viral structural proteins. In normal, healthy somatic cells, their virus-related activities are epigenetically silenced through DNA and histone methylation. In mice, they are transiently expressed at the 2-cell stage (soon after the first cell division of the fertilized egg) and then suppressed. Suppression is a mechanism for controlling gene expression (i.e., RNA polymerization from a DNA sequence) that requires additional energy.

When the mechanism is compromised by energy stress or mechanistic deregulation, retroelements are transcribed. Often, it forms dsRNA. The sign of an RNA virus. However, it derived from its own DNA.

In the absence of viral infection, the viral-sensing machinery is activated in certain stress-related situations. Inflammation is initiated. This inflammation is private in a single cell, intermittent, and low-grade. Unlike a viral infection, the clothes in the closet will not change much. Probably, only adjacent neighbour cells notice an intermittent low-grade inflammation. However, there is no apparent abnormality to make a phone call to recruit further help. The neighbours give support to compensate for the situation.

Nothing gets immediately worse because it does not spread rapidly—no big deal at any point. Initially, the cell with low-grade intermittent inflammation is just a single cell. The process of cell division takes time. Nothing is acute—slow, sporadic, low-grade inflammation. Our homeostatic system compensates for it to keep the regular operation.

In many cancer cases, patients have no symptoms until the very late stages. Most symptoms are not directly related to the cancer itself, but rather to the secondary effects of the tumour (i.e., an abnormal cell mass), which can cause physical obstructions in vital organs. 

This is the reason why cancer is called a silent killer, because the early pathogenic changes are compensated for in homeostasis. Although there is low-grade, chronic, intermittent inflammation, there is no direct pain sensation. Pain sensation is evoked in the later stages due to acute dysfunctions caused by physical obstructions.

Inflammation is like a fire alarm — a message to take specific actions, including evacuation. Frequent false alarms make people off guard and may turn the alarm off or reduce its volume. Everyone gets used to the false alarms and adopts living with them. Chronic low-grade inflammation is troublesome because it prompts our system to adopt new conditions rather than directly addressing the causes. Without erasing the causes, our homeostatic system keeps compensating for the problems without our cognition. Although the range of compensation is large, but limited, it will eventually collapse. Not all challenges can be absorbed.

Imagine a mountain bike. Tires can absorb shocks. Also, a front suspension and a shock absorber under the saddle.  A rider’s legs and arms also absorb shocks. The neck also helps maintain the head’s position. The roughness of the road, the bike's speed, the rider’s weight, and the rider's skills matter. Shock absorbance is compensation. If a flat tire, a rusted suspension, or the rider's weight is too much, the range of shock absorption will be limited. If the balance is not maintained (i.e. compensated), the rider will fall off the bike.  That is equivalent to death.

Life is a cyclical momentum within nested circuits. Each circuit is a complex network with high compensatory ability. When a lower-level circuit is collapsed, the next upper circuit compensates for it. Mild chronic inflammation with cell-cycle entry, which is Cancer, gradually compromises the layers of our compensatory system. When it reaches the top circuit due to the lower bottom problem, our life ends.