LL-37 in Respiratory Immunity

Lung Defense Peptides

3.55% lower FEV1

COPD patients with plasma cathelicidin below 50 ng/ml had 3.55% lower lung function, linking low LL-37 levels to more severe airway disease.

Burkes et al., Chronic Obstructive Pulmonary Diseases, 2020

Burkes et al., Chronic Obstructive Pulmonary Diseases, 2020

View as image

Your airways produce their own antibiotic. LL-37, the only cathelicidin antimicrobial peptide made by humans, is secreted by airway epithelial cells, stored in neutrophil granules, and released onto the mucosal surface of the respiratory tract. It kills bacteria, neutralizes viruses, recruits immune cells, and selectively eliminates infected epithelial cells while leaving healthy neighbors intact. When LL-37 levels drop, respiratory infections become more severe, and diseases like COPD worsen. For context on how the respiratory tract coordinates multiple antimicrobial peptides, see Defensins in Your Lungs: The First Line of Airway Defense.

How LL-37 Reaches the Airway Surface

Tjabringa et al. (2005) reviewed LL-37's multifaceted role in pulmonary infection and inflammation, establishing the framework for understanding how the peptide functions in the respiratory tract.^[1]

LL-37 arrives at the airway surface through two routes. The first is constitutive secretion by airway epithelial cells. These cells express the cathelicidin gene (CAMP) and secrete the inactive precursor hCAP-18, which is cleaved to release the active LL-37 peptide. This provides a baseline antimicrobial coating on the airway surface at all times.^[1]

The second route is rapid deployment from neutrophils. LL-37 is stored at high concentrations in the specific (secondary) granules of neutrophils. When these immune cells are recruited to the airway during infection, they release their granule contents, flooding the site with LL-37. This creates a surge of antimicrobial activity that supplements the constitutive epithelial production.^[1]

Beyond direct antimicrobial activity, LL-37 in the lung acts as a chemoattractant for neutrophils, eosinophils, and monocytes via formyl-peptide receptor-like 1 (FPRL1). It also modulates dendritic cell differentiation and macrophage function, bridging the innate and adaptive immune systems. This dual role, simultaneously killing pathogens and coordinating the immune response, makes LL-37 far more than a simple antibiotic peptide. For more on its immunomodulatory effects, see LL-37's Dual Role: Anti-Inflammatory and Pro-Inflammatory Effects.

Killing Infected Cells While Sparing Healthy Ones

Barlow et al. (2010) discovered one of LL-37's most remarkable properties in the lung: it selectively kills infected airway epithelial cells while leaving uninfected cells intact.^[2]

When airway epithelial cells were infected with Pseudomonas aeruginosa (a major pathogen in cystic fibrosis and hospital-acquired pneumonia), LL-37 promoted apoptosis (programmed cell death) of the infected cells. Critically, the same concentration of LL-37 did not trigger apoptosis in uninfected cells.^[2]

This selective killing serves a defensive purpose. Infected epithelial cells that harbor intracellular bacteria are essentially compromised outposts. If they continue to survive, they provide a protected niche for bacterial replication. By triggering their apoptosis, LL-37 eliminates these niches and exposes the bacteria to direct antimicrobial attack.

Apoptosis (as opposed to necrosis) is a controlled form of cell death that does not release inflammatory contents into the surrounding tissue. This is important in the lung, where excessive inflammation can be as damaging as the infection itself. LL-37's ability to remove infected cells without amplifying tissue-destructive inflammation represents a sophisticated defense strategy that goes beyond simple pathogen killing.^[2]

Antiviral Activity: LL-37 vs. Respiratory Viruses

Currie et al. (2013) demonstrated that LL-37 has direct antiviral activity against respiratory syncytial virus (RSV), one of the most common causes of lower respiratory tract infections in infants and the elderly.^[3]

In epithelial cell cultures, LL-37 produced multiple antiviral effects simultaneously:

• Prevented virus-induced cell death in epithelial cultures
• Significantly inhibited the production of new infectious viral particles
• Diminished the spread of infection from cell to cell
• Showed antiviral effects directed at both viral particles and host epithelial cells^[3]

The mechanism involved both direct effects on viral particles and modulation of host cell responses. LL-37 appeared to interfere with viral attachment and entry, while also enhancing the cells' own antiviral defenses.

Pashaie et al. (2024) provided ultrastructural evidence for how cathelicidins disable viruses. Using transmission electron microscopy, they showed that LL-37 directly altered virus morphology and caused aggregation of viral particles, physically preventing them from infecting cells.^[5] At non-toxic concentrations of 5 and 10 micromolar, LL-37 significantly reduced viral infection in both co-incubation (simultaneous exposure) and pre-incubation setups, suggesting the peptide works both by disabling free virus and by preparing cells to resist infection.^[5]

Fluorescently labeled LL-37 was observed entering cells, suggesting a possible intracellular immunomodulatory component to its antiviral action beyond the direct physical disruption of viral particles.^[5]

These findings extend to other respiratory pathogens. LL-37 has demonstrated antiviral activity against influenza virus and, more recently, SARS-CoV-2, though the clinical significance of these in vitro observations remains uncertain. For a deeper look at LL-37's antiviral mechanisms in the lung, see Cathelicidins and Respiratory Viruses: LL-37's Antiviral Role in Lungs.

LL-37 Levels Track with Lung Disease Severity

Two clinical studies have examined the relationship between circulating cathelicidin levels and respiratory disease, with complementary findings.

Majewski et al. (2018) measured serum LL-37 concentrations in patients with bacterial lung infections. Patients with community-acquired pneumonia, hospital-acquired pneumonia, and chronic infections all had significantly elevated serum LL-37 compared to healthy controls.^[4] The highest levels were observed in community-acquired pneumonia, consistent with an acute mobilization of the cathelicidin defense during active infection. This elevation confirms that LL-37 production ramps up systemically during lung infections, not just locally at the site of infection.

Burkes et al. (2020) took the opposite approach, examining what happens when cathelicidin levels are low. In 1,609 participants from the SPIROMICS COPD cohort, plasma cathelicidin below 50 ng/ml was independently associated with 3.55% lower percent-predicted FEV1 (a standard measure of lung function).^[6] For every 10 ng/ml decrease in cathelicidin, there was a 0.65% additional decrease in lung function.

The association was independent of age, sex, race, BMI, smoking status, and other confounders. Notably, low cathelicidin was not independently associated with longitudinal lung function decline or COPD exacerbation frequency, suggesting it marks disease severity at a given time point rather than predicting future trajectory.^[6]

Together, these studies suggest a bidirectional relationship: the respiratory system produces more LL-37 during acute infection (an appropriate defense response), while chronically low LL-37 is associated with worse baseline lung function (possibly reflecting an inadequate defense). Whether low cathelicidin causes worse lung function or simply reflects it remains an open question.

The Vitamin D Connection

Vitamin D is the most potent known inducer of cathelicidin/LL-37 gene expression. The cathelicidin gene contains a vitamin D response element (VDRE) in its promoter region, and 1,25-dihydroxyvitamin D3 (the active form of vitamin D) directly activates LL-37 transcription.

This molecular link has generated significant clinical interest. Vitamin D deficiency is common in populations with high respiratory infection rates (the elderly, institutionalized individuals, people at northern latitudes). If vitamin D supplementation could boost LL-37 production and thereby enhance airway antimicrobial defense, it would represent a simple, inexpensive intervention. For more on this pathway, see Vitamin D and LL-37: Why Sunlight Boosts Your Antimicrobial Peptides.

Clinical trial evidence for this approach is mixed. Some trials show modest benefits of vitamin D supplementation for respiratory infection prevention in deficient individuals, while others show no effect. The heterogeneity may partly reflect that vitamin D's immunomodulatory effects extend far beyond cathelicidin induction, making it difficult to isolate the LL-37-specific contribution.

What the Evidence Does Not Support

LL-37 supplementation for respiratory infections. No clinical trial has tested exogenous LL-37 (inhaled or systemic) for treating or preventing respiratory infections in humans. The in vitro and animal data are encouraging, but the leap to clinical application faces delivery challenges (peptide stability, distribution in the airways, potential toxicity at high concentrations) and regulatory hurdles.

LL-37 as a COPD treatment. The association between low cathelicidin and worse lung function in COPD is correlational. Whether raising cathelicidin levels would improve COPD outcomes has not been tested. The disease process in COPD involves structural lung destruction that antimicrobial peptides cannot reverse.

Broad-spectrum antiviral protection. While LL-37 shows in vitro activity against RSV, influenza, coronaviruses, and other viruses, the concentrations required may exceed what can be achieved in the airway through natural production or supplementation. The clinical relevance of these antiviral effects during actual human infections remains unproven.

Species generalizability. Pashaie et al. (2024) showed that cathelicidins from different species have very different antiviral potencies. None of the four porcine cathelicidins tested had any activity against the virus in their study, while human LL-37 and chicken CATH-B1 were effective.^[5] This species specificity means animal model results cannot be directly extrapolated to predict human cathelicidin function.

The Bottom Line

LL-37 defends the airways through a layered strategy: direct bacterial killing on the mucosal surface, selective apoptosis of infected epithelial cells, antiviral activity through physical disruption of viral particles, and immune cell recruitment via chemotactic signaling. Clinical data shows that LL-37 levels rise during acute lung infections and that chronically low levels are associated with worse COPD outcomes. The vitamin D-cathelicidin axis offers a potential therapeutic target, but clinical evidence for vitamin D supplementation improving respiratory outcomes through LL-37 induction is inconsistent. No human trial has tested exogenous LL-37 for respiratory disease.

Frequently Asked Questions

What does LL-37 do in the lungs?

LL-37 is an antimicrobial peptide produced by airway epithelial cells and neutrophils that provides multiple layers of respiratory defense. It kills bacteria through membrane disruption, neutralizes viruses by physically damaging viral particles, selectively triggers death of infected airway cells while sparing healthy ones, and recruits immune cells to the site of infection.^[1][2]

Can LL-37 kill viruses in the respiratory tract?

In laboratory studies, LL-37 showed antiviral activity against respiratory syncytial virus (RSV), preventing virus-induced cell death and reducing viral spread in epithelial cultures.^[3] Electron microscopy showed LL-37 physically disrupts viral particles and causes them to aggregate.^[5] Whether these in vitro effects translate to meaningful antiviral protection during human respiratory infections has not been clinically demonstrated.

Is low LL-37 linked to worse lung disease?

In a study of 1,609 COPD patients, plasma cathelicidin (LL-37) below 50 ng/ml was independently associated with 3.55% lower lung function (FEV1). Every 10 ng/ml decrease corresponded to 0.65% lower lung function. The association was independent of smoking status, age, and BMI. This suggests low LL-37 tracks with disease severity, though whether it is a cause or consequence remains unclear.^[6]

Does vitamin D increase LL-37 in the lungs?

The cathelicidin gene has a vitamin D response element, and active vitamin D (1,25-dihydroxyvitamin D3) directly increases LL-37 production. This is the strongest known inducer of cathelicidin expression. Clinical trials of vitamin D supplementation for respiratory infection prevention in deficient individuals have shown mixed results, with some modest benefits but inconsistent findings overall.

How does LL-37 selectively kill infected cells?

Barlow et al. (2010) showed that LL-37 promoted programmed cell death (apoptosis) in airway epithelial cells infected with Pseudomonas aeruginosa while leaving uninfected cells unharmed. This selective killing removes the protected niches where bacteria replicate intracellularly. Apoptosis is a controlled death that avoids releasing inflammatory contents, limiting collateral tissue damage.^[2]

Are LL-37 levels elevated during pneumonia?

Patients with bacterial lung infections had significantly elevated serum LL-37 compared to healthy controls, with the highest levels in community-acquired pneumonia. This elevation reflects systemic mobilization of the cathelicidin defense during active respiratory infection, confirming that the body ramps up LL-37 production beyond just the local infection site.^[4]