Inflammation is our body’s ancient, built-in first responder. When injury or infection strikes, a complex alarm system sounds, summoning immune cells to the scene to contain the threat and initiate repairs. But what happens when this fire alarm gets stuck, blaring endlessly? This chronic, smoldering inflammation is now recognized as a key driver of many of our most formidable diseases, from arthritis to cancer and heart disease. At the heart of this paradox lies a class of molecules known as "alarmins," which act as the initial danger signals. Today, we zoom in on one of the most prominent and enigmatic of these alarmins: S100A9. Is it a loyal guardian protecting us from harm, or a rogue agent fanning the flames of chronic disease?
At its core, S100A9 is a small protein with a crucial job: sensing and binding to calcium and zinc ions [1]. This ability is granted by its characteristic "EF-hand" structural motifs, which act like molecular claws. Upon grabbing calcium, S100A9 undergoes a conformational change, transforming its shape to interact with other proteins.
However, S100A9 rarely acts alone. It finds its true purpose when it partners with a sibling protein, S100A8, to form a stable heterodimer known as calprotectin. Think of it as a two-part security key; only when both parts come together is the system fully armed. This S100A8/A9 complex is the primary functional form of the protein, abundantly produced by myeloid immune cells like neutrophils and monocytes [2].
Once released from activated or dying cells at a site of damage, calprotectin acts as a powerful extracellular signal. It functions like a molecular bullhorn, binding to receptors like Toll-like receptor 4 (TLR4) and the Receptor for Advanced Glycation End products (RAGE) on nearby cells. This docking event triggers a cascade of pro-inflammatory signals, amplifying the initial alarm and recruiting more immune cells to the battlefield [2, 3]. But it also has another trick up its sleeve: calprotectin is a potent antimicrobial agent. By tightly binding and sequestering essential metals like zinc and manganese, it effectively starves invading bacteria and fungi, a defense mechanism known as nutritional immunity [4].
The story of S100A9 is a classic tale of a hero whose strengths, when unchecked, become its greatest weakness. In the right context—an acute infection or a wound—its ability to rally the immune system is vital for survival. The problems begin when the "off" switch fails.
In autoimmune diseases like rheumatoid arthritis, S100A9 is a key villain. It floods the joints, perpetuating a vicious cycle of inflammation that leads to cartilage and bone destruction [4]. In cardiovascular disease, the story is just as grim. High levels of S100A9 are found in unstable atherosclerotic plaques, the kind most likely to rupture and cause a heart attack or stroke. It actively promotes inflammation within the vessel walls, contributing to the disease's progression [2].
Perhaps its most complex role is in cancer. Initially, inflammation helps fight tumors. However, chronic inflammation driven by S100A9 can create a tumor-promoting microenvironment. It helps recruit myeloid-derived suppressor cells (MDSCs), a type of immune cell that shields the tumor from the body's defenses, effectively acting as a bodyguard for the cancer [3]. This dual role makes S100A9 a fascinating, albeit challenging, subject in oncology. Its influence even extends to the brain, where it is implicated in the neuroinflammation associated with conditions like Alzheimer's disease [6].
Because S100A9 is released directly at the site of inflammation, its levels in blood, stool, or other bodily fluids can serve as a direct readout of inflammatory activity. This has made it an incredibly valuable clinical tool.
The most established use is in gastroenterology, where measuring fecal calprotectin has become a standard, non-invasive test to diagnose and monitor inflammatory bowel disease (IBD) [5]. For rheumatologists, S100A9 has proven to be a more reliable biomarker for disease activity in rheumatoid arthritis than traditional markers like C-reactive protein (CRP), especially for patients on certain biologic therapies [4]. Its potential applications are rapidly expanding, with research showing its promise as a biomarker for predicting outcomes in septic shock [8], assessing cardiovascular risk [2], and even differentiating early stages of cognitive impairment [6].
Given its central role in so many diseases, a critical question arises: can we therapeutically target S100A9 to quell the inflammatory fire? The answer, increasingly, appears to be yes. Several exciting strategies are now being explored.
Small molecule inhibitors, such as a class of compounds called quinoline-3-carboxamides (e.g., tasquinimod), have shown they can bind directly to S100A9. This prevents it from interacting with its receptors, effectively muting its pro-inflammatory and tumor-promoting signals. These drugs have already shown clinical activity in cancers like prostate cancer and multiple myeloma [3]. Another approach involves using monoclonal antibodies designed to specifically neutralize circulating S100A9, a strategy that has shown efficacy comparable to established anti-TNFα therapies in preclinical models of arthritis [4].
Perhaps the most innovative idea is the development of a therapeutic vaccine against S100A9. Early studies in animal models have shown that this can generate a sustained antibody response that inhibits thrombosis (blood clotting) without increasing the risk of bleeding—a major hurdle in anti-thrombotic therapy [7].
Developing these novel inhibitors and biologics requires robust methods for producing and screening target proteins. The complexity of proteins like S100A9 can make traditional expression challenging. This is where platforms like Ailurus vec®, which use self-selecting vectors to rapidly screen thousands of genetic designs for optimal protein expression, could accelerate the discovery of better production methods and, ultimately, new drugs.
From a humble alarm molecule to a master regulator of inflammation and a prime therapeutic target, S100A9 continues to reveal new layers of complexity. As we learn to modulate its activity with greater precision, we may soon be able to turn the dial down on chronic inflammation, transforming the prognosis for millions of patients worldwide.
Ailurus Bio is a pioneering company building bioprograms, which are genetic codes that act as living software to instruct biology. We develop foundational DNAs and libraries to turn lab-grown cells into living instruments that streamline complex procedures in biological research and production. We offer these bioprograms to scientists and developers worldwide, empowering a diverse spectrum of scientific discovery and applications. Our mission is to make biology a general-purpose technology, as easy to use and accessible as modern computers, by constructing a biocomputer architecture for all.
