S100A8S100A9

S100A8S100A9, commonly known as calprotectin, is a heterodimer formed by the two calcium-binding S100 proteins, S100A8 and S100A9. This complex is abundant in neutrophils and monocytes and is released during inflammatory responses, contributing to both intracellular signaling and extracellular antimicrobial activity.

Both subunits belong to the S100 family and contain EF-hand calcium-binding motifs. Upon calcium binding, S100A8 and S100A9 interact to form a stable heterodimer; the complex can assemble into higher-order oligomers, including tetramers. Calprotectin binds and sequesters transition metals such as zinc and manganese, limiting microbial growth.

Externally, calprotectin acts as a damage-associated molecular pattern, engaging pattern recognition receptors such as TLR4 and RAGE to promote cytokine production and recruiting immune cells. It also functions as an antimicrobial effector and a chemoattractant for neutrophils and monocytes, contributing to the amplification of inflammatory responses.

Clinically, elevated calprotectin levels are used as a biomarker of inflammation. Fecal calprotectin is a noninvasive marker for gastrointestinal inflammation and is widely used to monitor inflammatory bowel disease and differentiate IBD from irritable bowel syndrome. Serum calprotectin can be elevated in sepsis, autoimmune diseases, and other inflammatory states. Measurements are typically done by ELISA.

Expression of S100A8 and S100A9 is upregulated by inflammatory signals, including TNF-α and IL-1β, and is driven by NF-κB–dependent pathways. The proteins are among the most abundant S100 family members in neutrophils, and their release can occur through active secretion or cell damage, contributing to the local and systemic inflammatory milieu.