Inflammation has a bad reputation, and we typically think of it as something that needs to be shut down as quickly as possible. However, inflammation itself isn’t usually the problem. It is an essential part of the body's response to injury, infection, and other threats. Inflammation helps mobilize immune cells, remove damaged material, and protect tissues when something goes wrong.
What matters just as much is what happens after inflammation has done its job. Inflammation has largely been viewed as a process that needs to be stopped or suppressed. Yet research over the past several decades has revealed another layer of the body's response: inflammation has an active resolution process that helps bring the response to a close and supports the return toward normal tissue function. The. key molecules involved in this process include specialized pro-resolving mediators (SPMs).
(Note: Sometimes, SPMs are also referred to as pro-resolving mediators (PRMs). PRMs are direct precursors (or building blocks) of SPMs; that is, PRMs are molecules in the final stages before being converted into SPMs in the body. We’ll describe PRMs more in a future installment of this series.)
A New Understanding of Inflammation: Active Resolution through SPMs
The discovery of SPMs in the early 2000s helped change how scientists understand the inflammatory process. Research led by scientists including Harvard Medical School's Charles Serhan, PhD, identified previously unrecognized lipid-derived molecules (SPMs) that appeared during the later stages of an inflammatory response. Rather than promoting or (conversely) blocking inflammation, these molecules helped resolve it.1
That finding was revolutionary in the field of immunology. Previously, inflammation was seen as a process that passively “faded away” after the initial inflammatory response. However, Dr. Serhan’s work helped us understand that inflammation is brought to its conclusion (or turned off) through an active, well-regulated biological process called resolution, and SPMs are critical molecules that drive this transition from an inflammatory response toward restoration and homeostasis.1
When SPMs coordinate the cellular events involved in bringing inflammation to an appropriate conclusion, they tell the immune system to reduce excess inflammation, clear damaged cells and cellular debris, and support tissue restoration.2 SPMs can be thought of as the “all clear” flag, telling immune cells that it’s time to stop fighting and time to start cleaning up and rebuilding. Scientists call this “resolution physiology.”1
Unlike traditional treatments or drugs that aim to suppress (or completely block) inflammation, SPMs help guide the inflammatory response toward natural resolution. This distinction matters because inflammation serves essential protective functions; the goal isn't to eliminate the body's ability to respond to a threat, but to help the response reach a conclusion.
How the Body Resolves Inflammation
It can help to think of inflammation as having three overlapping phases.
1. Alarm
An injury, infection, or other threat occurs. The body recognizes that something is wrong and initiates an inflammatory response. Chemical signals recruit immune cells and other immune components to the affected area.
2. Defense
Immune cells enter the tissue and begin addressing the problem. They can help eliminate pathogens, remove damaged cells, and contain the threat.
3. Resolution
Once the body has addressed the threat, it needs to shift gears. This is where SPMs and other pro-resolving mediators become especially important. They help limit further recruitment of inflammatory cells, promote the clearance of cells that are no longer needed, and coordinate the transition toward tissue repair and restoration (i.e., healing). 1
This is why scientists describe resolution as an active biological program, rather than simply the absence of inflammation. The inflammatory response doesn't just switch off on its own; the body uses a network of signals to coordinate what happens next.
Where Do SPMs Come From?
One of the most interesting aspects of SPM biology is that many SPMs are closely related to (and derived from) something many of us have heard of before: omega-3 fatty acids, particularly DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid).
Importantly, DHA and EPA are not SPMs themselves. Instead, fatty acids like DHA and EPA serve as building blocks (or precursors) that the body converts into SPMs through a series of enzymatic reactions.
(Note: DHA and EPA aren’t the only building blocks for SPMs. Other SPMs are derived from different fatty acids, including arachidonic acid (AA) and docosapentaenoic acid (DPA). However, SPMs related to DHA and EPA are the most intensely researched because of their connection to omega-3 nutrition.)
The process is significantly more complex than this simple sequence suggests, involving multiple enzymes, intermediates, and regulatory pathways. But the basic concept helps explain why researchers are interested not only in omega-3 intake, but also in the specific molecules produced from these fatty acids.1,3
The Major Families of SPMs
SPMs aren't a single molecule. They are a family of specialized “lipid mediators” that can be grouped into several major families, each with different structures, precursors, and biological activities. Here, we’ll focus on three families: resolvins, protectins, and maresins.2
Resolvins
Resolvins are one of the most extensively studied SPM families. They include E-series resolvins, derived from EPA, and D-series resolvins, derived from DHA. Examples include Resolvin E1 (RvE1) and Resolvin E2 (RvE2), which arise from EPA, and Resolvin D1 (RvD1) and Resolvin D2 (RvD2), which arise from DHA. Extensive research has investigated these four resolvins for their roles in regulating inflammatory activity, immune-cell behavior, and tissue recovery, indicating that they direct the resolution phase of inflammation, act as immune balancers, support cellular clean-up, and promote healthy recovery.1
Protectins
Protectins are SPMs derived from DHA. One particularly well-studied member is protectin D1 (PD1), which is also known as neuroprotectin D1 (NPD1) when produced in neural tissues. As their name suggests, protectins have attracted interest for their potential roles in protecting tissues while also participating in inflammation resolution. NPD1 is also of strong interest for its role in brain, retinal, and overall nervous system health, supporting recovery, repair, and protection.1
Maresins
Maresins are another family of SPMs derived from DHA. Macrophages, immune cells that play an essential role in clearing damaged cells and cellular debris, produce maresins. Researchers have identified Maresin 1 (MaR1) as especially involved in the transition from inflammation to tissue repair and regeneration, making it particularly connected to healing.1
RvE1, RvE2, RvD1, RvD2, PD1 (NPD1), and MaR1 are likely the six most studied SPMs in the resolution physiology field. However, researchers continue to identify and study additional specialized pro-resolving mediators, including DPA-derived resolvins and other emerging mediator families and intermediates. Together, these molecules form a complex network of signals that help regulate how the body responds to inflammation and how it brings that response toward resolution.
SPMs at Work Throughout the Body
The same resolution pathways that clean up damaged tissue also play a role in how the body responds to everyday physical stress, maintains healthy tissues, and manages inflammation over time. SPMs help support this process throughout the body, including in:
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Joints and mobility
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Heart health
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Brain health
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Metabolic health
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Healthy aging and overall cellular health
We'll take a closer look at these connections throughout this series, including a deeper dive into SPMs and brain health in Part 3.
When Inflammation Doesn’t Resolve
A well-running inflammatory process is crucial to maintaining a healthy body. The challenge is sustaining the right balance — responding appropriately to the initial threat, then resolving the response when the job is finished.
That balance can become harder to maintain when the body is repeatedly exposed to inflammatory stresses or when inflammatory signaling persists longer than it should. This raises an important question: What happens when inflammation doesn't resolve as effectively as it should?
That is: What if inflammation remains unresolved?
A concept often used to describe this chronic, low-grade inflammation is inflammaging. Researchers are investigating how age-related changes in inflammatory and pro-resolving pathways may contribute to this persistent inflammatory state.
In the next part of this series, we'll explore what inflammaging means, why unresolved low-grade inflammation becomes more common with age, and why our ability to resolve inflammation may be key to healthy aging.
References:
1. Serhan, C. N. & Levy, B. D. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. Journal of Clinical Investigation 128, 2657–2669 (2018).
2. Chiang, N. & Serhan, C. N. Specialized pro-resolving mediator network: an update on production and actions. Essays Biochem. 64, 443–462 (2020).
3. Basil, M. C. & Levy, B. D. Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat. Rev. Immunol. 16, 51–67 (2016).