Several antimicrobial proteins trigger inflammation, but the one most studied for this dual role is LL-37, a cathelicidin peptide produced by immune cells and skin cells throughout the body. LL-37 kills bacteria directly, yet it also activates inflammatory pathways that, when dysregulated, contribute to conditions like psoriasis and rosacea. It’s not alone: defensins and S100 proteins also provoke inflammatory responses, each through distinct mechanisms.
LL-37: The Best-Known Inflammatory Trigger
LL-37 is the primary active form of the human cathelicidin family. Your body produces it as an inactive precursor protein, then enzymes called kallikreins (particularly kallikrein 5) clip it into its active form on surfaces like the skin. Once activated, LL-37 punches holes in bacterial membranes to kill pathogens. But it also acts as a powerful alarm signal for the immune system.
LL-37 recruits immune cells to the site of infection by functioning as a chemoattractant, pulling in mast cells, dendritic cells, and other white blood cells. It also stimulates the production of signaling molecules like IL-8 and MCP-1, which call in even more reinforcements. On top of that, LL-37 has been linked to activation of the NLRP3 inflammasome, a molecular complex inside cells that processes and releases the potent inflammatory signal IL-1β. In bladder epithelial cells infected with a common strain of E. coli, the NLRP3 inflammasome was found to be essential for triggering LL-37 release, suggesting a feedback loop between the peptide and the inflammasome.
How LL-37 Drives Psoriasis
LL-37’s inflammatory power becomes a problem in autoimmune skin disease. In psoriasis, levels of LL-37 are abnormally high in affected skin. Damaged or dying skin cells release fragments of their own DNA, which would normally be ignored by the immune system. But LL-37 binds to this cell-free DNA and forms a complex that changes everything: the complex gets delivered into a type of immune cell called plasmacytoid dendritic cells, where it activates a sensor called TLR9. This triggers a cascade of inflammatory cytokine production and T cell activation that sustains the characteristic red, scaly plaques of psoriasis.
In other words, LL-37 converts harmless self-DNA into something the immune system treats as a threat. This mechanism has made the LL-37/DNA complex a target for experimental therapies. Researchers have tested nanoparticles designed to break up this complex in mice and monkeys, reducing psoriatic inflammation.
LL-37’s Role in Rosacea
Rosacea involves a related but distinct problem. In affected skin, the activity of kallikrein 5 and other proteases is abnormally high. This leads to excessive cleavage of cathelicidin into LL-37 and additional smaller peptide fragments that don’t normally appear in healthy skin. These variant fragments trigger inflammation, redness, and the visible blood vessel changes (telangiectasias) characteristic of rosacea. The issue isn’t just overproduction of the peptide itself but also abnormal processing that generates fragments with amplified inflammatory activity.
Defensins and Cytokine Release
Defensins are another major family of antimicrobial proteins that trigger inflammation. Human beta-defensin 2 (HBD-2) is particularly potent. When researchers exposed human blood cells to HBD-2, it stimulated dose-dependent release of a broad range of inflammatory signals: IL-6, IL-8, IL-10, MCP-1, IL-1β, and several others including RANTES and MIP-1β. HBD-2 was consistently the most active defensin tested.
HBD-3, by comparison, was relatively quiet. After 18 hours of exposure, it produced only modest increases in IL-8 and MCP-1. This selectivity matters because it shows that not all antimicrobial proteins provoke the same degree of inflammation.
Beyond cytokine release, defensins physically recruit immune cells to infection sites. Alpha-defensins like HNP-1 and HNP-2 attract monocytes, T cells (both CD4+ and CD8+), neutrophils, and mast cells. Beta-defensins HBD-1 and HBD-2 pull in memory T cells and immature dendritic cells through a specific receptor called CCR6. HBD-2, HBD-3, and HBD-4 also cause mast cells to release their granules, produce prostaglandin D2, and mobilize calcium inside the cell, all of which amplify the local inflammatory response.
S100 Proteins Act as Danger Signals
S100A8 and S100A9 are antimicrobial proteins that pair together to form a complex called calprotectin. Unlike LL-37 and defensins, which mainly kill microbes by disrupting their membranes, S100A8/A9 primarily triggers inflammation by acting as a damage-associated molecular pattern (DAMP). This means the immune system treats it like a danger signal released from injured tissue.
The complex binds to two receptors on cell surfaces: TLR4 and RAGE. When S100A8/A9 locks onto these receptors, it activates two major inflammatory signaling cascades inside the cell (the NF-κB and MAPK pathways), which drive the production of inflammatory mediators like TNF-α and IL-6. This mechanism has been well documented in brain inflammation, where S100A8/A9 activates immune cells called microglia and worsens damage to the cells that insulate nerve fibers. Elevated S100A8/A9 levels are associated with Alzheimer’s disease, lupus affecting the brain, and other neuroinflammatory conditions.
Because S100A8/A9’s inflammatory effects depend on binding to TLR4 and RAGE, researchers have developed small-molecule inhibitors like tasquinimod and paquinimod that block this interaction, reducing the downstream inflammatory response.
Why Antimicrobial Proteins Cause Inflammation
The overlap between killing microbes and triggering inflammation isn’t a design flaw. Recruiting immune cells, releasing cytokines, and activating inflammasomes are all part of a coordinated defense: antimicrobial proteins soften up the invaders while simultaneously calling in backup. Problems arise when the system stays on too long or fires without an actual infection. In psoriasis, rosacea, lupus, and other inflammatory conditions, the same proteins that protect against bacteria end up sustaining chronic inflammation against the body’s own tissues.
Of all the antimicrobial proteins involved, LL-37 is the most versatile inflammatory trigger. It activates inflammasomes, recruits nearly every type of immune cell, induces cytokine production, and converts harmless self-DNA into an autoimmune stimulus. Defensins and S100 proteins contribute through their own pathways, but LL-37 sits at the center of the most inflammatory cascades.