We Keep Treating Inflammation. What Is It?

I often ask the students I work with a question that sounds easier than it is:

“What is inflammation?”

The answers usually include pain, swelling, and immune cells.

Then I ask: “Suppose a researcher examines a sample from a painful tendon and finds no obvious immune-cell infiltrate. Could inflammatory activity still be present?”

That usually makes us pause.

We use this word constantly. We explain symptoms with it, prescribe medications for it, and sometimes tell patients their problem has nothing to do with it. I include myself among those who have used it more comfortably than precisely.

What do we mean by inflammation?

Most of us picture inflammation as a sequence: tissue is injured, blood vessels respond, fluid enters the area, and immune cells arrive. The tissue may become warm, swollen, and painful.

That is a useful picture of an acute inflammatory response. But it is not a checklist that every inflammatory process must satisfy.

More broadly, inflammation is a coordinated biological response to infection, injury, or tissue stress. Cells detect a disturbance, exchange signals, and change their behavior. The response serves protective functions, although it can also persist and contribute to damage. Its features vary with the trigger, tissue, and stage of the process. Medzhitov, 2008.

Studies assess different aspects of that response. Some count immune cells. Others measure cytokines or the activity of genes involved in inflammatory pathways.

Those findings are related, but they are not interchangeable. Before concluding that two studies disagree, we need to ask what each actually measured.

What does that mean for a painful tendon?

Many of us learned that chronic tendinopathy is “degenerative, not inflammatory.” Part of that explanation came from tissue studies showing collagen disorganization without the inflammatory-cell infiltrate we expected.

But an absence of obvious infiltrating cells does not tell us everything the tissue is doing.

Tenocytes, the cells that maintain the tendon’s collagen matrix, can also produce inflammatory signals. In a laboratory study, cultured human tendon cells increased their release of molecules including IL-6 after exposure to selected inflammatory stimuli. No immune cells had to be added to those cultures for that response to occur. Stolk et al., 2017.

The tendon’s resident cells were participating in inflammatory signaling.

There is also evidence beyond cell culture. Research examining human chronic Achilles tendinopathy has identified both immune-cell populations and inflammatory pathway activity. Dakin et al., 2018.

So chronic tendinopathy can involve inflammatory activity. Degenerative changes and inflammatory signaling can coexist.

This is not unique to tendons. Fat cells, for example, also release signaling molecules such as IL-6. Inflammatory signaling is not exclusive to immune cells. Fried et al., 1998.

For the patient with a painful tendon, the harder questions are how much that activity contributes to symptoms and whether targeting it will help.

What I take back to the clinic

This makes me more careful with the explanation, “It is degeneration, not inflammation.”

Structural changes tell us something about the tendon. They do not fully describe its cellular activity or rule out an inflammatory contribution.

It also changes how I interpret a paper claiming that inflammation is absent. Before accepting that conclusion, I want to know what the investigators looked for and what their methods could have missed.

The reverse deserves the same care. Detecting an inflammatory signal does not establish that it is driving the patient’s pain or that suppressing it will improve the outcome. Treatment still requires evidence of clinical benefit.

Inflammation is a response. Before saying it is present or absent, we should be clear about which part of that response we have actually assessed.