Part 2: Reactive Oxygen Species and the Immune Blueprint: A Functional Map of Inflammation
- Bowie Matteson
- Aug 19
- 13 min read
Part 1 looked at the qualities of iron that made it an ideal piece in the creation of cellular energy. We learned about how ubiquitous iron's reactivity was in the animal kingdom and the impacts that had on nature's competitive forces for a treasured natural resource.
We also learned about the inner workings of the human body and how it uses iron: from oxygen delivery and cellular respiration to bolstering host defenses against pathogens. Iron is a force to be reckoned with.
Seeing how powerful iron was and the protective measures the body put in place to conserve and insulate its supply stood out to me. So much care put into a single resource. A resource so seldomly spoken about in the medical world. With how reactive iron was and how hard the body worked to channel that energy, it made me curious about what happened when iron's force wasn't properly channeled. What does iron damage control look like? Much like how the gasoline in your car is the reason it moves, there is an implicit understanding that it can also be used to burn it to the ground. What happens when iron's volatility is experienced outside of its appropriate roles? These questions led me into the world of inflammation. Part 2 is dedicated to understanding inflammation as a hallmark of misappropriated iron. While not all inflammation is iron-laden, it's important to understand the inner-workings of the inflammatory process. From there we come to see how quickly iron can add fuel to pre-existing flames, or serve as the proverbial spark to the incendiary conditions of poor cellular hygiene.
What is inflammation?
Inflammation is one of the most commonly used words in health and medicine today. It’s been tied to every major chronic condition. The World Health Organization (WHO) states that chronic inflammatory diseases are the most significant cause of death in the world and pose the greatest threat to the future of human health.
And while it affects nearly all of us to some degree, society’s understanding of what inflammation actually is is remarkably low. If you were to ask anyone on the street today what inflammation was, I don’t know that you’d get 2 of the same answer. Or rather, you’d get a list of symptoms of inflammation, as opposed to its true definition.
Swollen, inflamed, itchy, blood-rushed, angry, irritated.
It’s like asking someone to describe the wind, or the color red.
Inflammation is commonly known as the resulting redness, swelling, pain, and/or a feeling of heat in an area of the body. It can supportive as well as destructive; A functional means of disposing of byproducts of basic cell function and a protective reaction to injury, disease, or irritation of the tissues.
Akin to the body's relationship to stress, some inflammation is necessary as a means of healthy cell hygiene. It's all of matter of volume and context.
The Cellular Clean-Up Crew: PMNs, ROS, and the Immune Response
What are the things—across the spectrum of function, injury, disease, and irritation—that elicit an immuno-protective response?
One of the central triggers is a category of molecules called reactive oxygen species (ROS). Though often framed negatively, ROS are vital signaling agents in our immune defense and tissue repair systems. Their production and downstream effects reflect the body’s attempt to maintain cellular hygiene—identifying what doesn't belong, cleaning it up, and rebuilding what was damaged in the process.
Meet the First Responders: PMNs (Polymorphonuclear Neutrophils)
When tissue is injured—by physical trauma (like scraping your knee) or chemical exposure (like touching bleach)—our body mobilizes a specialized set of immune cells. One of the earliest to arrive on scene are neutrophils, a type of white blood cell known as a polymorphonuclear neutrophil (PMN) due to their multi-lobed nucleus.
These PMNs act as the frontline soldiers of the immune system. They are fast-acting, aggressive, and efficient. Their role is to:
Detect the presence of pathogens, damaged cells, or foreign material
Migrate rapidly to the site of distress
Engulf threats via phagocytosis
Release ROS and enzymes to break down invaders and compromised tissue
While other granulocytes like eosinophils and basophils participate in immune defense, especially against parasites or allergens, they are not considered PMNs. Neutrophils are the central figure in this first-wave response.
When you hear the words oxidative stress, free radicals or inflammatory markers, those are blanket terms for ROS.
ROS: From Weapons to Breadcrumbs
These PMNs are what we think of when we imagine white blood cells. They are the soldiers of our immunity, the army that identifies and targets threats within our system, neutralizing and removing the invader.
PMNs release reactive oxygen species (including superoxide, hydrogen peroxide, and hypochlorous acid) to kill bacteria, break down infected tissue, and digest cellular debris. These ROS act as chemical weapons, but they also serve a secondary purpose: they become signals.
Once the immediate threat is neutralized, the residual ROS act like breadcrumbs, marking areas of recent immune activity and cellular damage. These molecules are recognized by other cells—macrophages, fibroblasts, and signaling cascades—as a call for repair and regeneration.
In this sense, ROS are both destroyers and messengers—cleaning up the battlefield, then calling in the reconstruction crew.
Because addressing the threat is only one part of a complete response. An additional function beyond the removal of the threat is the signal for requiring repair. This duality in healing, confronting the attacker and addressing the wound, is an important distinction in addressing inflammation. Healing and ridding inflammation are not necessarily synonymous.
Inflammation: The Broader Immune Process
It's important to understand that inflammation is not just what happens after the battle. Inflammation is a whole-body orchestration that begins the moment immune activation is triggered.
It includes:
Vasodilation (expanding blood vessels to bring in more cells and nutrients)
Swelling (due to increased fluid and immune cell migration)
Pain and redness (from chemical signaling and nerve activation)
Fever and systemic response, if the stimulus is large enough
While PMNs serve as emergency responders, inflammation is the larger process that holds the perimeter, brings in resources, contains damage, and signals when it's time to repair and rebuild.
🧠 Putting It All Together: The Metaphor of the Burning Building
Imagine a burning building:
The PMNs are the firefighters, rushing in to contain the flames and prevent further destruction.
ROS are the water, foam, and damage caused in the act of fighting the fire—they do damage, but also mark where cleanup is needed.
Inflammation is the cleanup and renovation crew: they arrive not just to sweep away debris, but to reconstruct, reinforce, and rebuild.
This process is not passive. It’s intelligent, layered, and context-responsive—determined by the nature of the threat, the terrain of the tissue, and the body's ability to coordinate cleanup and renewal.
*Putting out the flames isn't the same thing as making the house livable. This is the relationship between PMNs (firefighters), the ROS they leave behind (the calls for rebuild), and inflammation (the rebuilding effort). *
🔁 Cellular Hygiene in Action
In principle the system is flawless. An automatically dispersed group of cells whose sole responsibility is to identify threats and preserve the well-being of your body. It removes the bad guys and facilitates restoration.
In a healthy system, the process is self-limiting: PMNs neutralize the threat, ROS signal repair, and inflammation resolves.
But when ROS production becomes excessive—or the body fails to resolve the cascade—the very molecules that signal for help can start to degrade healthy tissue, creating a feedback loop of damage and overreaction. This is where chronic inflammation, autoimmunity, and tissue degeneration can emerge.
In my mind, addressing inflammation is rediscovering that line of self-regulation and dysfunction. Right now inflammation is being vilified in broad strokes. How can we restore the innate systems meant to regulate ROS balance?
It's clear that this PMN-ROS response is not reserved for only epic battles with viruses and cancer cells. ROS are also a part of a much more mundane aspect of cellular health. They are natural byproducts of the metabolism of oxygen. Every second of every day, our cells are slowly emitting bits of ROS as a part of their daily work. There is a constant low-level amount of ROS present at the site of every healthy cell’s respiration. In this way, the mainstream assault on inflammation is short-sighted (or perhaps only one side of the coin).
Inflammation is a signal for taking out the trash. The cell needs the trash taken out regularly. Our "health", from an inflammation standpoint, is the degree of regularity that a cell's trash is disposed of. Think about it:
A healthy adult’s ROS load signals taking out the trash to maintain a clean and orderly cell.
A chronically inflamed ROS load is a hoarder’s house with smoke billowing out the windows.
From a logistics standpoint, with the ROS as a signal for repair, what happens if something is always under repair? If there are so many burning buildings that no matter how many firefighters and water we disperse, the resulting tarp-covered roofs, moldy floorboards and inhospitable conditions leave the home condemned.
So what exactly are these reactive oxygen species? Why is something designed to help us hurting us? What do they look like and why are they so destructive?
Identifying Reactive Oxygen Species
While ROS may or may not be a new term to you, it is worthwhile to to break it down just one
more time to identify exactly what we are looking for, chemically speaking. There are three main types of ROS known in the body:
Superoxide O2ᐨ = O2 + eᐨ
Hydrogen peroxide H2O2 (+O2) = 2Hᐩ + O2ᐨ + O2ᐨ
Hydroxyl Radicals •OH : Hydrogen peroxide in turn may be partially reduced, thus forming hydroxide ions and hydroxyl radicals (•OH): H2O2 + eᐨ → OH- + •OH
Their common ingredient, as noted in their name, is oxygen. Oxygen, like iron, is incredibly reactive. Like bringing life to a flame or causing your stored vegetables to brown, oxygen is an accelerant. In health, the term oxidize or oxidative stress goes hand in hand with an inflammatory response.
Moving forward, when we imagine the site of inflammation, its important to keep these specific molecules in mind. They belong on the proverbial WANTED poster; "free radicals" out on the loose.
While we now see that they are not inherently bad, fighting pathogens and signaling repair, its these reactive oxygen species—superoxide (O₂•⁻), hydrogen peroxide (H₂O₂), and hydroxyl radical (•OH)— that can serve as the seeds of destruction.
Like a controlled burn in a forest, ROS must be contained. Without boundaries, they consume what they were meant to prune.
🧬 ROS in Healthy Physiology: Precision Tools
🧼 1. Cellular Hygiene & Mitochondrial Maintenance
Superoxide is a natural byproduct of ATP production in mitochondria.
Normally, this is neutralized by superoxide dismutase (SOD) → converts O₂•⁻ into hydrogen peroxide (H₂O₂)
H₂O₂ is further broken down by catalase (in peroxisomes) or glutathione peroxidase, turning it into harmless water and oxygen.
🔧 In this context, ROS are like janitors: identifying worn-out proteins, oxidizing dysfunctional lipids, and flagging debris for removal.
🛡️ 2. Adaptive Immunity & Microbial Defense
Macrophages and neutrophils deliberately produce ROS via the NADPH oxidase system to kill invaders.
This “oxidative burst” floods infected or damaged tissue with superoxide and H₂O₂, making the environment inhospitable to pathogens.
After the threat is neutralized, anti-inflammatory signals (e.g., IL-10) restore balance and cleanup ensues.
🎯 In this role, ROS are like tactical weapons: deployed in short bursts, on clear targets, followed by disarmament.
So these ROS have well-defined roles in both daily cell happenings as well as acute defensive strategies. When we think of oxidative stress in the context of disease development, what is the tipping point of helpful to destructive? What are the factors that help maintain working order? What outside influences can drain the system of its ability to recover from oxidative stress?
🧨 When the Balance Breaks: From Acute to Chronic
When ROS generation outpaces the cell’s antioxidant defense systems, oxidative stress takes hold.
🚩 Key Stressors That Tip the Scale:
Mitochondrial dysfunction (iron overload, hypoxia, nutrient depletion)
Chronic immune activation (gut leakiness, infection, autoimmunity)
Environmental toxins (pesticides, heavy metals, plastics)
Nutrient deficiencies (e.g., low selenium, zinc, glutathione precursors)
📉 Under these conditions, SOD, catalase, and glutathione systems become overwhelmed or underproduced.
🧬 Corrective Systems in Healthy Cells vs. Breakdown in Disease
Corrective System | Healthy Cell Function | Disease State Breakdown |
Mitochondria | Controlled ROS signaling, ATP production | Excess leakage of superoxide, reduced efficiency |
SOD (superoxide dismutase) | Converts O₂•⁻ → H₂O₂ | SOD depleted or inactivated under chronic oxidative stress |
Catalase (peroxisomes) | Converts H₂O₂ → H₂O + O₂ | Peroxisomal burden exceeds capacity → H₂O₂ builds up |
Glutathione peroxidase (GPx) | Detoxifies H₂O₂ and lipid peroxides using glutathione (GSH) | GSH depletion leads to lipid membrane damage |
Macrophages | Clear debris, controlled ROS burst | Chronic activation = constant ROS + cytokine production |
Autophagy pathways | Remove damaged organelles and oxidized proteins | Blocked by ROS and mTOR overactivation |
⚖️ In a healthy system, there’s a check after every signal. In disease, the brakes fail—and the inflammatory flame burns on.
🧠 The ROS Switchblade
"In a healthy cell, ROS are like a switchblade—folded up and tucked away, pulled out only with intention and precision. In a sick cell, that blade is left open, waving in every direction, nicking everything it touches—including the cell itself."
🧯 How the Body Tries to Cool the Fire
Upregulates antioxidant response genes via Nrf2
Signals for mitophagy to eliminate damaged mitochondria
Mobilizes glutathione, vitamin C, vitamin E, selenium, and zinc as redox buffers
Inflammatory resolution via lipoxins, resolvins, and regulatory cytokines
But if ROS keep pouring in, these measures collapse, and chronic diseases like:
Diabetes
Atherosclerosis
Neurodegeneration
Autoimmune conditions...take root.
🗒️Important things to note:
🔹1. Not all ROS are created equal.
Hydrogen peroxide is the body's preferred ROS. This is because of H2O2's stability compared to superoxide and hydroxyl radicals.
ROS | Reactivity | Lifespan | Mobility | Damage Potential |
Superoxide (O₂•⁻) | Moderate | Microseconds | Local (mitochondria) | Limited; rapidly dismutated |
Hydrogen peroxide (H₂O₂) | Mild to moderate | Seconds (relatively stable) | Can diffuse across membranes | Signaling, but damaging at high levels |
Hydroxyl radical (•OH) | Extremely reactive | Nanoseconds | Doesn’t travel | Highest oxidative damage to DNA, lipids, proteins |
🔍 Why H₂O₂? It offers the cell a “buffer zone”—stable enough for redox signaling, but easily detoxified by catalase and glutathione peroxidase when levels rise. Superoxide and hydroxyl radicals don’t afford that luxury.
Hydrogen peroxide offers stability, greater signaling potential and a lower risk of damage to the cell. Superoxide and hydroxyl radicals do not offer that same safety. Keep this in mind in the chapters to come.
🔹 2. Mitophagy: The Mitochondrial Safety Valve
Mitophagy is the selective breakdown of mitochondria (AKA mitochondrial autophagy). Mitochondria are the ground zero of ROS production. The body's natural reflex for mitophagy in times of increased ROS reflects that. Being the primary sources of energy in the cell, the metabolic output of mitochondria necessitates an equivalent anti-oxidant capacity. Whether that means specific enzymes like catalase and superoxide dismutase, or entire systems like mitophagy.
Why mitochondria are the source:
~90% of cellular oxygen ends up in mitochondria
Electrons leak from Complexes I & III → superoxide production
Iron–sulfur clusters and cytochromes increase redox volatility
Damaged mitochondria leak even more ROS
What mitophagy does:
Tags dysfunctional mitochondria (via PINK1/Parkin) for degradation
Prevents runaway ROS generation (leading to domino-style mitochondria die-off)
Protects neighboring mitochondria and nuclear DNA from spillover
🔄 Healthy mitophagy = inflammation kept in check. Blocked or overwhelmed mitophagy = chronic oxidative signaling, inflammasome activation, and cellular degeneration.
When we hear about the role of mitochondria in health and disease, we need to think beyond the broad stroke of "mitochondrial dysfunction". What is specifically happening in the cell's power plants that is causing this ROS accumulation?
🔹 3. The Liver: Gatekeeper of the Fireline
The liver is not just a detox organ—it’s a battlefield commander in the war against oxidative stress.
Key Roles:
GSH production: It’s the main hub of glutathione synthesis, our master antioxidant
Iron metabolism: Stores, releases, and recycles iron via ferritin, hepcidin, and transferrin
Toxin handling: Cytochrome P450s generate ROS as part of detoxification
Nutrient storage and conversion: Cofactors for antioxidant enzymes (zinc, selenium, B6, etc.)
Kupffer cells (resident macrophages) are key in modulating inflammatory tone
🧯 When the liver is burdened—whether by toxins, pathogens, or iron—it can no longer regulate the redox balance. This creates spillover inflammation, pushing oxidative stress into the bloodstream, brain, pancreas, or gut.
An overtaxed liver is unable to effectively handle the oxidative stress load. With a steady intake of pro-inflammatory toxins and a lack of nourishment to bolster its antioxidant capacity, the liver begins to compensate. This leads to inefficiencies, altered filtration and resource reallocation, all of which contribute to the inflammatory load if not addressed in a timely fashion.
When we acknowledge the liver's central role in oxidative stress regulation we have to respect its central role in our digestive, hormonal and excretory systems. With its "upstream" role in the cascade of inflammation, how does this reframe disease pathology? Where in the order of operations does something like beta cells and the pancreas fall when we consider the liver as the primary source of ROS regulation?
We will revisit the liver in later sections.
🔹 4. High-Metabolic Organelles & Their Inflammatory Footprint
Where in the cell itself is ROS most prevalent? We mentioned mitochondria before but there are others worth our attention. Endoplasmic reticulum, as the protein-folding factories of the cell, are always producing and monitoring metabolic outputs. Waste management organelles like lysosomes and peroxisomes are specifically designed to collect and neutralize any circulating ROS for redox balance.
Organelle | Function | Iron-ROS Interaction |
Mitochondria | ATP, ETC, major ROS production | Contains iron–sulfur clusters and cytochromes |
Peroxisomes | Detox long-chain FAs, neutralize H₂O₂ | Home of catalase to manage H₂O₂ from metabolism |
Endoplasmic Reticulum | Protein folding, redox buffering | Generates ROS via disulfide bond formation, loaded with SOD1 |
Lysosomes | Breakdown of iron-containing structures | Release free iron during degradation, catalyzing Fenton chemistry |
Macrophages | ROS bursts for immunity | Balance between pathogen killing and bystander tissue damage |
When we begin to look at specific disease states like diabetes and multiple sclerosis, we can work backwards from the systems we see failing and trace what is happening within cells and organs.
Conclusion: From Inflammation to Iron – The Terrain Beneath the Fire
Inflammation is not the enemy—it is a biological intelligence system designed to recognize threat, initiate cleanup, and restore order. At the heart of this response are PMNs, the white blood cell first responders who unleash reactive oxygen species (ROS)—potent molecular tools that neutralize danger and signal for repair. These ROS, while essential to immune defense and tissue renewal, can also spiral into self-destruction when their production exceeds the body’s ability to contain and resolve the damage.
Through the lens of cellular hygiene, we explored how the body balances firepower with finesse: how it uses ROS to destroy invaders, but also relies on antioxidant systems, organelle defenses, and intercellular signaling to clear the battlefield and restore function. We framed inflammation as both a firefight and a construction project, emphasizing that health is not the absence of ROS, but rather the ability to generate and neutralize them in proportion to need.
But beneath the sparks of this immunological fire lies a deeper fuel source—one that can either support renewal or ignite pathology. That source is iron. When regulated, iron is essential for oxygen transport, energy production, and immune resilience. But when left unchecked, it becomes the matchstick to the inflammatory flame—catalyzing reactions like the Fenton and Haber-Weiss cycles that escalate oxidative damage, rupture membranes, and perpetuate immune chaos.
In the next section, we’ll explore how iron’s dual nature makes it both a nutrient and a liability—and how its mismanagement often sits at the root of chronic inflammation, metabolic collapse, and cellular degeneration.
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