S100A8, also known as calgranulin A, is a calcium-binding protein from the S100 family. Produced by specific immune cells, it is part of the body’s innate defense system where it functions as an internal alert signal. When tissues are injured or an infection occurs, S100A8 is released to help initiate and regulate the body’s inflammatory response, which is designed to protect the body.
The Function of S100A8 in the Immune System
S100A8 rarely acts alone, most often binding with a partner protein called S100A9 to form a stable complex known as calprotectin. This complex makes up a significant portion of the proteins in neutrophils, a type of white blood cell that acts as a first responder to infection or injury. The S100A8/A9 complex is stored inside these cells and released when they are activated by pathogens or damage.
Once released, the S100A8/A9 complex functions as an “alarmin,” a type of Damage-Associated Molecular Pattern (DAMP) that signals cellular damage to the immune system. This alarm function occurs when the complex binds to receptors on other immune cells, like Toll-like receptor 4 (TLR4). This interaction triggers a signaling cascade that amplifies the inflammatory response and attracts more neutrophils to the site.
In addition to signaling, the calprotectin complex has direct antimicrobial properties through a process called nutritional immunity. It inhibits the growth of bacteria and fungi by binding to and sequestering transition metals like zinc and manganese from the environment. This deprives microbes of necessary nutrients, effectively starving them and preventing their spread.
S100A8 as a Clinical Biomarker
In medicine, S100A8 is measured as a clinical biomarker, which is a substance whose concentration can indicate a disease state. Because the S100A8/A9 calprotectin complex is released in high amounts during inflammation, its levels in bodily fluids serve as a proxy for inflammatory activity.
Elevated calprotectin levels signal that an inflammatory process is occurring. Clinicians measure this protein in blood for systemic inflammation or in stool to identify inflammation within the gastrointestinal tract. The standard laboratory method for this measurement is an enzyme-linked immunosorbent assay (ELISA).
S100A8/A9 is a non-specific marker of inflammation, meaning high levels confirm inflammation is present but do not identify the cause. Various conditions, from infections to autoimmune diseases, can increase calprotectin. The test is therefore used as part of a broader diagnostic workup to guide further investigation.
Association with Chronic Inflammatory Diseases
The measurement of S100A8/A9 is well-established in managing chronic inflammatory diseases, particularly Inflammatory Bowel Disease (IBD), which includes Crohn’s disease and ulcerative colitis. A non-invasive fecal calprotectin test detects intestinal inflammation, helping physicians differentiate IBD from non-inflammatory conditions like Irritable Bowel Syndrome (IBS). This distinction can help avoid invasive procedures like colonoscopies, as patients with IBS have normal calprotectin levels.
For patients already diagnosed with IBD, monitoring fecal calprotectin levels allows clinicians to assess disease activity and response to treatment. The relevance of S100A8/A9 extends to other autoimmune conditions. In Rheumatoid Arthritis (RA), levels of S100A8/A9 are elevated in the blood and the synovial fluid of affected joints, often correlating with disease severity and joint damage.
Similarly, in psoriasis, a chronic autoimmune skin condition, S100A8 is found at high levels in psoriatic plaques where it contributes to the inflammatory feedback loop. Elevated serum levels of S100A8/A9 are also associated with psoriatic arthritis, a related condition involving both skin and joint inflammation. Elevated S100A8/A9 has also been noted in other inflammatory states, such as cardiovascular disease.
The Complex Role of S100A8 in Cancer
The relationship between S100A8 and cancer is a double-edged sword, as its function varies depending on the cancer type and the tumor microenvironment. Its role is not simply pro-tumor or anti-tumor, adding complexity to its study in oncology.
On one hand, S100A8 can contribute to cancer progression. As a pro-inflammatory molecule, it can help create an environment that supports tumor growth, invasion, and metastasis by recruiting immune cells and promoting certain signaling pathways. In some colorectal and breast cancers, high S100A8/A9 levels are associated with a poorer prognosis.
On the other hand, S100A8 can also exhibit anti-tumor effects. In some experimental settings, the S100A8/A9 complex has been shown to induce apoptosis (programmed cell death) in certain tumor cells. This effect may be mediated through mechanisms like zinc chelation, which can disrupt cellular processes in cancer cells.
Targeting S100A8 as a Therapeutic Strategy
Due to the association between elevated S100A8/A9 levels and the severity of many inflammatory diseases, researchers are exploring it as a target for new treatments. The rationale is that blocking the protein’s activity could alleviate disease symptoms and prevent tissue damage. This approach is a promising area of therapeutic development.
Several strategies are being investigated to inhibit the calprotectin complex. One approach involves small-molecule inhibitors designed to block its interaction with receptors like TLR4. Another strategy uses monoclonal antibodies to neutralize the S100A8/A9 complex, preventing it from triggering inflammatory cascades. For example, studies in animal models of arthritis show that antibodies against S100A9 can reduce disease severity.
These therapeutic concepts are still largely in the research and preclinical development stages. They hold potential for creating more targeted treatments for diseases like rheumatoid arthritis, IBD, and psoriasis. By directly intervening in the inflammatory pathway driven by S100A8, these therapies could offer a more precise way to manage chronic inflammation.