LL-37 and Vitamin D: The Sunshine Connection

LL-37 and Cathelicidin

1 billion vitamin D deficient

An estimated one billion people worldwide have insufficient vitamin D levels, potentially impairing their production of LL-37, the only human cathelicidin antimicrobial peptide.

Amrein et al., European Journal of Clinical Nutrition, 2020

Amrein et al., European Journal of Clinical Nutrition, 2020

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In 2006, a team led by Philip Liu published a paper in Science that changed how immunologists think about vitamin D. They showed that when human macrophages detect Mycobacterium tuberculosis through Toll-like receptors, the cells upregulate both the vitamin D receptor (VDR) and the enzyme that converts circulating 25-hydroxyvitamin D into its active form, 1,25-dihydroxyvitamin D. The active vitamin D then binds the VDR and directly induces expression of cathelicidin, the precursor of the antimicrobial peptide LL-37, which kills the intracellular bacteria.^[1] That single finding connected sunlight, a fat-soluble vitamin, and an ancient antimicrobial defense system into one pathway.

The implications extended beyond tuberculosis. Liu's group also found that serum from African-American individuals, who have higher rates of vitamin D deficiency due to melanin-mediated UV absorption, was less effective at supporting cathelicidin induction in immune cells.^[1] The finding suggested that population-level differences in vitamin D status could directly affect innate antimicrobial defense. This article covers the full vitamin D-LL-37 axis: the molecular pathway, the evidence from infections and inflammatory diseases, and where the science stands today. For a broader look at LL-37 itself, see LL-37: The Only Human Cathelicidin and Why It's So Versatile. For how LL-37 physically destroys pathogens, see How LL-37 Disrupts Bacterial Membranes and Biofilms. For a comparative view, see Cathelicidins Across Species: What Animal Versions Teach Us.

How vitamin D activates LL-37 production

The vitamin D-cathelicidin pathway begins with a vitamin D response element (VDRE) in the promoter region of the CAMP gene, which encodes the cathelicidin precursor protein hCAP-18. When 1,25-dihydroxyvitamin D (calcitriol, the hormonally active form) binds the intracellular vitamin D receptor, the VDR forms a heterodimer with retinoid X receptor alpha (RXRa). This complex binds the VDRE and activates transcription of CAMP.^[2]

Svensson et al. (2016) showed in human keratinocytes that vitamin D-induced cathelicidin upregulation specifically requires RXRa and involves histone acetylation at the CAMP promoter, indicating epigenetic regulation of the pathway.^[2] This is not a simple on/off switch. The magnitude of LL-37 induction depends on the availability of both vitamin D and the transcriptional machinery.

The translated protein, hCAP-18 (18 kDa human cationic antimicrobial protein), is stored in neutrophil granules and epithelial cell secretory vesicles. Upon secretion, extracellular proteinase 3 cleaves hCAP-18 to release the active 37-amino-acid peptide LL-37, named for its two N-terminal leucine residues and 37-residue length.^[3]

One critical detail: this VDRE in the CAMP promoter is present in primates but absent in mice and most other mammals. This explains why vitamin D-cathelicidin studies in standard mouse models have historically been difficult to interpret, and why Lowry et al. (2020) developed a transgenic mouse carrying the human CAMP gene to study the pathway.^[4] Those humanized mice showed vitamin D-dependent LL-37 expression and improved wound healing, confirming the pathway's functional significance.

The TLR-vitamin D-cathelicidin circuit

Liu's 2006 Science paper revealed that the vitamin D-cathelicidin pathway is not constitutively active. It is triggered by immune activation.^[1]

When macrophages detect pathogen-associated molecular patterns (PAMPs) through Toll-like receptors, two things happen simultaneously: TLR signaling upregulates expression of CYP27B1 (the enzyme that converts 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D) and the VDR itself. This means the immune cell both creates more active vitamin D locally and becomes more sensitive to it. The locally produced calcitriol then activates the CAMP gene, producing LL-37 that can kill the invading pathogen.

This circuit has a bottleneck: circulating 25-hydroxyvitamin D. If serum 25(OH)D levels are insufficient, the immune cell cannot produce enough local calcitriol to drive adequate cathelicidin expression, regardless of how strongly TLRs are signaling. This is the molecular basis for why vitamin D deficiency compromises innate antimicrobial defense.

Chung et al. (2020) published a comprehensive review of the vitamin D-cathelicidin axis, describing it as sitting "at the crossroads between protective immunity and pathological inflammation during infection."^[5] They noted that the same pathway that enhances antimicrobial killing can also modulate inflammatory responses, with LL-37 acting as an immunomodulatory molecule that dampens excessive cytokine production while maintaining antimicrobial activity.

The elegance of this circuit is in its specificity. Not all vitamin D effects on immunity flow through cathelicidin. Vitamin D regulates over 200 genes involved in immune function, including effects on T cell differentiation, macrophage activation, and cytokine production. But the cathelicidin pathway is unique because it is directly transcriptional (VDR binding to a defined VDRE), it is triggered by pathogen detection (TLR activation), and it produces an effector molecule (LL-37) that physically destroys pathogens. This directness makes it the most clearly actionable vitamin D-immune axis for therapeutic intervention. For a broader view of how antimicrobial peptides fight bacteria, see How Antimicrobial Peptides Kill Bacteria: Pore Formation Explained.

Tuberculosis: where the connection was discovered

The vitamin D-LL-37 axis was first characterized in the context of tuberculosis for historical and biological reasons. The observation that sunlight and cod liver oil helped TB patients predates modern immunology by over a century. Liu et al. (2006) provided the molecular explanation: vitamin D-induced cathelicidin production enables macrophages to kill intracellular M. tuberculosis.^[1]

Al-Jaberi et al. (2022) extended this work by examining macrophages from a patient with a rare genetic disorder affecting VDR signaling. These macrophages showed reduced vitamin D-induced cathelicidin production and impaired killing of M. tuberculosis compared to healthy controls, providing genetic evidence that the VDR-cathelicidin pathway is required for effective anti-tuberculosis immunity.^[6]

Guevara et al. (2020) reviewed the broader interface between vitamin D, host immunity, and streptococcal infections, finding that vitamin D deficiency impairs production of multiple antimicrobial peptides including LL-37 and lactoferrin, helping explain higher infection susceptibility in vitamin D-deficient populations.^[7]

The tuberculosis data is strong but not without complexity. Clinical trials of vitamin D supplementation as adjunctive TB therapy have shown mixed results, likely because the relationship between serum 25(OH)D, local calcitriol production, cathelicidin expression, and bacterial killing involves multiple variables that a single supplement cannot uniformly address. Patients who are severely vitamin D deficient appear most likely to benefit, while those with adequate baseline levels show minimal additional cathelicidin induction from supplementation. This dose-response ceiling is consistent with the molecular pathway: once VDR-RXRa complexes are saturated at the CAMP promoter, additional vitamin D substrate cannot drive further transcription.

The TB connection also has evolutionary significance. Mycobacterium tuberculosis has co-evolved with humans for tens of thousands of years. The fact that the pathogen's detection through TLR2/1 specifically activates the vitamin D-cathelicidin pathway suggests strong selective pressure for this defense mechanism. Populations that migrated to higher latitudes with lower UV exposure (and therefore lower vitamin D synthesis) may have been at particular disadvantage, a hypothesis supported by the historical geography of tuberculosis epidemics and the long-observed clinical benefits of sunlight exposure (heliotherapy) in TB sanatoriums before the antibiotic era.

Respiratory infections and asthma

Beyond tuberculosis, the vitamin D-LL-37 axis has been studied in common respiratory infections. Ramos-Martinez et al. (2018) conducted a study in asthma patients supplemented with vitamin D and found a significant reduction in respiratory infections. The clinical improvement correlated with increased serum levels of both LL-37 and the anti-inflammatory cytokine IL-10.^[8] This finding is particularly relevant because asthma patients have impaired airway antimicrobial defenses and are vulnerable to respiratory pathogens.

Crane-Godreau et al. (2020) hypothesized that vitamin D deficiency exacerbates COVID-19 through suppression of LL-37, noting that the populations most affected by severe COVID-19 (elderly, obese, dark-skinned individuals) overlap substantially with those at highest risk for vitamin D deficiency.^[9] Roth et al. (2025) provided direct biochemical evidence: vitamin D-inducible LL-37 binds the SARS-CoV-2 Spike protein and accessory proteins ORF7a and ORF8, suggesting a mechanism by which LL-37 could interfere with viral entry and function.^[10]

LL-37's antiviral activity is not limited to coronaviruses. Tripathi et al. (2013) showed that LL-37 inhibits influenza A viruses through a mechanism distinct from surfactant protein D, directly disrupting viral membranes and reducing infectivity.^[11] Barlow et al. (2011) demonstrated that LL-37 both kills influenza directly and enhances host antiviral immune responses, increasing survival in a mouse model of influenza infection.^[12]

These findings must be interpreted carefully. In vitro antiviral activity does not guarantee clinical relevance, and the concentrations of LL-37 used in many experiments exceed physiological levels. The COVID-19 association between vitamin D deficiency and disease severity, while biologically plausible through the LL-37 mechanism, involves multiple confounding variables (age, comorbidities, socioeconomic factors) that observational studies cannot fully control. However, the convergence of in vitro binding data (Roth 2025), in vivo mouse models (Barlow 2011), epidemiological associations, and a clear molecular pathway makes the vitamin D-LL-37 antiviral axis one of the better-supported connections in the antimicrobial peptide field.

Skin diseases: atopic dermatitis and beyond

The skin is one of the largest reservoirs of cathelicidin, and the vitamin D-LL-37 connection has significant dermatological implications.

Connell et al. (2025) published a systematic review examining cathelicidin expression in atopic dermatitis (AD) and the therapeutic potential of vitamin D. They found that AD patients consistently show reduced cathelicidin expression in affected skin, which contributes to their susceptibility to skin infections, particularly Staphylococcus aureus colonization. Vitamin D supplementation upregulated cathelicidin expression across multiple studies, reducing infection risk.^[13]

Cabalin et al. (2023) demonstrated this clinically in children with atopic dermatitis, showing that oral vitamin D supplementation modulated epidermal expression of both the VDR and cathelicidin.^[14] The study provided direct evidence that systemic vitamin D supplementation can alter local antimicrobial peptide production in the skin. This connects to the broader role of antimicrobial peptides in shaping the microbiome, where LL-37 and other peptides help maintain the balance between commensal and pathogenic bacteria at barrier surfaces.

The vitamin D-cathelicidin relationship in skin is not always straightforward. Atazadeh et al. (2020) found increased LL-37 levels in vitiligo through a pathway that appeared independent of vitamin D receptor signaling, suggesting alternative regulatory mechanisms exist.^[15] This is a reminder that while vitamin D is the best-characterized inducer of cathelicidin, it is not the only one.

Wound healing and tissue repair

LL-37's role extends beyond pathogen killing. The peptide promotes wound healing through multiple mechanisms: stimulating cell migration, promoting angiogenesis, and modulating inflammation at wound sites.

Xi et al. (2024) demonstrated that LL-37 promotes wound healing in diabetic mice by regulating TFEB-dependent autophagy, addressing the impaired wound healing that is a major clinical problem in diabetes.^[16] Su et al. (2022) developed nanofiber dressings that codeliver 1,25-dihydroxyvitamin D3 and a CYP24A1 inhibitor (which prevents vitamin D degradation) to wound sites, promoting cathelicidin production and wound closure simultaneously.^[17]

Lowry et al. (2020) used their transgenic mouse model carrying the human CAMP gene to show that vitamin D-induced LL-37 expression improved wound healing outcomes, providing the first in vivo evidence in a mammalian model that vitamin D-dependent cathelicidin production has functional wound-healing consequences.^[4]

The wound healing connection raises practical questions about vitamin D status in surgical and trauma patients. Vitamin D deficiency is common in hospitalized populations, and the evidence suggests this deficiency could impair both antimicrobial defense and tissue repair at wound sites through the cathelicidin pathway. The nanofiber approach developed by Su et al. is particularly noteworthy because it addresses a central challenge in vitamin D-cathelicidin therapeutics: systemic vitamin D supplementation raises levels throughout the body, but wound healing requires high local LL-37 concentrations. Delivering vitamin D directly to the wound site with an inhibitor of the enzyme that degrades it (CYP24A1) maximizes local cathelicidin production where it is most needed.

Sorour et al. (2022) tested a related approach in dermatology, using intralesional vitamin D injections for verruca vulgaris (common warts). The injections increased local cathelicidin (LL-37) expression in the treated tissue, and warts resolved at a higher rate than in controls.^[19] The result supports the principle that local vitamin D administration can drive local cathelicidin production with therapeutic effect, though the mechanism in wart clearance likely involves immune activation against the virus rather than direct antimicrobial killing.

Vitamin D deficiency: the global scope of the problem

The clinical significance of the vitamin D-LL-37 axis depends on how widespread vitamin D deficiency actually is. A 2023 pooled analysis of 7.9 million participants across multiple countries found that 15.7% of the global population has serum 25(OH)D below 30 nmol/L (severe deficiency), and substantially higher proportions fall below the 50 nmol/L threshold considered insufficient for optimal health.

Prevalence varies dramatically by latitude, skin pigmentation, age, and lifestyle. Populations at 20-40 degrees north latitude showed the highest deficiency rates, with 84.9% below 75 nmol/L. Elderly, institutionalized, and obese individuals are disproportionately affected. Fabisiak et al. (2024) examined the relationship between vitamin D receptor expression, cathelicidin, and the iron-regulating peptide hepcidin in the context of intestinal inflammation, finding interconnected regulatory networks that connect vitamin D status to both antimicrobial defense and iron metabolism.^[18]

The overlap between populations with high vitamin D deficiency and populations with elevated infectious disease burden is striking but does not by itself prove causation. The vitamin D-cathelicidin axis provides a plausible molecular mechanism, and intervention studies like Ramos-Martinez (2018) provide supporting clinical evidence, but the relationship between vitamin D supplementation and infectious disease outcomes at the population level remains an area of active investigation.

What the evidence does and does not show

The molecular pathway linking vitamin D to LL-37 production is well-established. The evidence that this pathway matters for antimicrobial defense comes from multiple lines: cell biology, animal models, genetic studies, and clinical observations. Keshri et al. (2025) published a comprehensive review in the International Journal of Antimicrobial Agents cataloging LL-37's multifaceted roles from combating infections to cancer immunity, confirming that the vitamin D-cathelicidin axis is one of the best-characterized pathways in innate immune regulation.^[3]

The limitations are real. Clinical trials of vitamin D supplementation for infectious diseases have produced inconsistent results. This likely reflects the complexity of translating a cell-level mechanism to whole-organism outcomes: cathelicidin expression depends on local vitamin D conversion (not just serum levels), VDR expression varies by tissue and disease state, and LL-37 is one of many effector molecules in the immune response. A person's cathelicidin response to vitamin D supplementation depends on their baseline VDR expression, their inflammatory state, and their individual capacity for local vitamin D activation.

The absence of the VDRE from the mouse CAMP promoter means that decades of mouse studies missed the vitamin D-cathelicidin connection entirely. Only with the development of humanized transgenic models has it become possible to study the pathway in a living mammal. This is a significant limitation of the existing preclinical literature and means that many older studies of vitamin D and immunity were conducted in animals where the most direct antimicrobial mechanism does not operate.

There is also the question of tissue specificity. LL-37 is expressed in neutrophils, macrophages, epithelial cells of the skin, lungs, and gastrointestinal tract, and in keratinocytes. The vitamin D-dependent regulation operates in all these cell types, but the baseline expression levels, the magnitude of induction, and the proteolytic processing environment differ by tissue. A vitamin D intervention that successfully increases cathelicidin in blood monocytes may not produce the same effect in airway epithelium or skin keratinocytes. This tissue-level variability complicates the interpretation of serum LL-37 measurements as a proxy for tissue-level antimicrobial defense and may partly explain the inconsistent clinical trial results.

The dual nature of vitamin D-regulated LL-37

The same peptide that kills bacteria and viruses can, when overexpressed or improperly processed, drive pathological inflammation. In psoriasis, LL-37 complexes with self-DNA fragments released from damaged keratinocytes, creating structures that activate plasmacytoid dendritic cells through TLR9. This triggers an autoimmune inflammatory cascade that perpetuates the disease. In rosacea, excessive LL-37 processing by kallikrein 5 produces pro-inflammatory peptide fragments that cause the characteristic facial erythema and papules.^[5]

This dual nature has implications for any strategy to boost LL-37 production. Vitamin D supplementation that increases cathelicidin in someone with psoriasis could theoretically worsen their skin disease, even while improving their antimicrobial defense. The clinical literature has not systematically addressed this trade-off. Chung et al. (2020) emphasized that the context of LL-37 expression, including the proteolytic environment, the presence of danger signals, and the specific tissue, determines whether the peptide acts protectively or pathologically.^[5]

The vitamin D regulatory mechanism may serve partly as a natural brake on this system. By making LL-37 production dependent on both immune activation (TLR signaling) and vitamin D availability, the body limits constitutive cathelicidin expression. This two-signal requirement prevents the kind of runaway LL-37 production that could trigger inflammatory disease in the absence of actual infection.

For the broader landscape of antimicrobial peptides as alternatives to antibiotics, the vitamin D-cathelicidin axis represents one of the most promising natural antimicrobial systems, but one that operates within a carefully regulated context that any therapeutic approach must respect.

The Bottom Line

The vitamin D-LL-37 axis is a direct molecular link between a vitamin, an antimicrobial peptide, and the innate immune system. The pathway is well-characterized at the molecular level: TLR activation triggers local vitamin D conversion, which activates VDR signaling, which induces cathelicidin transcription, which produces LL-37. The clinical translation is supported by studies in tuberculosis, respiratory infections, skin diseases, and wound healing, though population-level intervention trials remain mixed. Given that vitamin D deficiency affects a substantial fraction of the global population, understanding this pathway has broad implications for infectious disease susceptibility.

Frequently Asked Questions

Does vitamin D directly increase LL-37 levels?

Active vitamin D (1,25-dihydroxyvitamin D) binds the vitamin D receptor, which forms a complex with retinoid X receptor alpha and activates the CAMP gene that encodes the LL-37 precursor protein hCAP-18. Svensson et al. (2016) demonstrated this requires RXRa and involves epigenetic changes at the gene promoter. The pathway is direct and transcriptional, not indirect or correlative. However, circulating 25-hydroxyvitamin D must first be converted to its active form locally by CYP27B1, meaning serum vitamin D levels do not translate linearly to LL-37 production.

What is the relationship between vitamin D deficiency and infections?

Vitamin D deficiency impairs production of LL-37, the body's only cathelicidin antimicrobial peptide. Liu et al. (2006) showed that serum from vitamin D-deficient individuals poorly supported cathelicidin induction in immune cells. Ramos-Martinez et al. (2018) found that vitamin D supplementation in asthma patients reduced respiratory infections alongside increased LL-37 levels. The molecular mechanism is established, though large-scale clinical trials of vitamin D for infection prevention have produced variable results depending on baseline deficiency levels and infection types.

Is LL-37 the only antimicrobial peptide regulated by vitamin D?

LL-37 is the most directly and strongly vitamin D-regulated antimicrobial peptide, with a vitamin D response element in its gene promoter. Vitamin D also influences expression of beta-defensins and other innate immune effectors, but the CAMP gene (encoding LL-37) contains the clearest and most well-characterized VDRE. Guevara et al. (2020) noted that vitamin D deficiency impairs production of multiple antimicrobial factors including LL-37 and lactoferrin, but the cathelicidin pathway is the primary one driven by direct VDR-mediated transcription.

Can vitamin D supplements boost LL-37 for immune support?

Clinical studies show that vitamin D supplementation can increase circulating LL-37 levels, particularly in individuals who are deficient at baseline. Cabalin et al. (2023) demonstrated that oral vitamin D increased cathelicidin expression in the skin of children with atopic dermatitis. The magnitude of the response depends on baseline vitamin D status, VDR expression, and the specific tissue involved. Supplementation in people with adequate vitamin D levels may not produce a proportional increase in cathelicidin because the pathway has regulatory limits.

Why don't regular mouse studies work for vitamin D and LL-37 research?

The vitamin D response element (VDRE) in the CAMP gene promoter is present in primates but absent in mice and most other mammals. Standard laboratory mice do not upregulate cathelicidin in response to vitamin D the way humans do. Lowry et al. (2020) created transgenic mice carrying the human CAMP gene to overcome this limitation, creating the first animal model where vitamin D-induced LL-37 expression could be studied in a living organism. This species difference means decades of mouse-based vitamin D immunity research missed the cathelicidin mechanism entirely.

Does LL-37 have antiviral activity beyond antibacterial effects?

LL-37 has documented antiviral activity against influenza, coronaviruses, and other enveloped viruses. Tripathi et al. (2013) showed LL-37 inhibits influenza A through direct viral membrane disruption. Roth et al. (2025) demonstrated that LL-37 physically binds SARS-CoV-2 Spike protein and accessory proteins ORF7a and ORF8. Barlow et al. (2011) found that LL-37 both directly kills influenza and enhances host immune responses. These antiviral functions are separate from LL-37's antibacterial pore-forming activity, confirming the peptide's broad-spectrum antimicrobial role.