How LL-37 Activates Neutrophils and Dendritic Cells

LL-37

6+ receptors

LL-37 activates immune cells through at least six distinct receptors, coordinating neutrophil recruitment, survival, and dendritic cell polarization.

Scott et al., Journal of Immunology, 2002

Scott et al., Journal of Immunology, 2002

View as image

Neutrophils arrive first at sites of infection, and dendritic cells decide what happens next. LL-37, the only human cathelicidin antimicrobial peptide, connects these two cell types through a signaling network that goes well beyond simple pathogen killing. As the pillar article on LL-37: The Immune Peptide That Does Everything describes, this peptide operates across antimicrobial, wound healing, and immunomodulatory domains. This article focuses specifically on how LL-37 recruits, activates, and regulates the two immune cell populations most central to bridging innate and adaptive immunity.

Scott et al. (2002) first demonstrated that LL-37 is not simply an antimicrobial agent but a multifunctional modulator of innate immune responses. Their work showed that LL-37 simultaneously suppresses LPS-driven macrophage activation while selectively recruiting neutrophils, monocytes, and T cells to infection sites.^[1] This dual capacity, dampening systemic inflammation while amplifying local immune recruitment, defines LL-37's role as an immune coordinator rather than a blunt antimicrobial weapon.

How LL-37 Recruits Neutrophils

LL-37 acts as a chemoattractant for neutrophils through the formyl peptide receptor-like 1 (FPRL1, also called FPR2). When LL-37 binds FPRL1 on neutrophil surfaces, it triggers intracellular calcium mobilization and directed cell migration toward the peptide source. This receptor is the same one that detects bacterial formylated peptides, meaning LL-37 essentially hijacks a pathogen-detection system to summon neutrophils to sites of tissue damage or infection even before bacteria are present.^[1]

The chemotactic activity operates at nanomolar concentrations, well below the micromolar levels required for direct antimicrobial killing. This concentration gradient means that LL-37 released from damaged epithelial cells or activated immune cells first functions as a recruitment signal, drawing neutrophils into the area, before reaching the higher local concentrations needed to kill pathogens directly.

Beyond FPRL1, LL-37 also signals through P2X7 (a purinergic receptor), CXCR2 (an interleukin-8 receptor), and the epidermal growth factor receptor (EGFR). Each receptor activates different downstream pathways, which explains why LL-37 produces a broader range of neutrophil responses than any single-receptor ligand could achieve.^[2]

Extending Neutrophil Survival

Neutrophils are normally short-lived cells, programmed to undergo apoptosis within 24 hours of leaving the bone marrow. This built-in self-destruct mechanism prevents excessive tissue damage from neutrophil proteases and reactive oxygen species. LL-37 overrides this program.

Bucki et al. (2010) reviewed the evidence showing that LL-37 prolongs neutrophil lifespan by upregulating the anti-apoptotic protein Bcl-XL while simultaneously downregulating the pro-apoptotic protein Bid. This survival signal is mediated primarily through FPRL1 and P2X7 receptor activation.^[2]

Extended neutrophil survival is a double-edged feature. During acute infection, keeping neutrophils alive longer enhances pathogen clearance. In chronic inflammation, the same mechanism contributes to tissue damage. Pinheiro da Silva and Machado (2017) framed this as the central paradox of cathelicidin biology: the same peptide that prevents neutrophil death during sepsis can perpetuate neutrophil-driven inflammation in autoimmune conditions like psoriasis and rheumatoid arthritis.^[3]

For the broader implications of this duality, see LL-37's Dual Role: Anti-Inflammatory and Pro-Inflammatory Effects.

Neutrophil Extracellular Traps and LL-37

When activated neutrophils undergo NETosis, they release web-like structures of chromatin, histones, and antimicrobial proteins called neutrophil extracellular traps (NETs). These structures trap and kill bacteria in the extracellular space. LL-37 is one of the antimicrobial peptides embedded within NETs, but its role extends beyond passive bacterial killing.

Herster et al. (2020) made a finding that revised the prevailing model of how NETs drive inflammation in psoriasis. The assumption had been that NET-associated DNA was the primary driver of autoimmune activation. Their work demonstrated that RNA, not DNA, is the critical nucleic acid component. NET-associated RNA (naRNA) complexed with LL-37 activated keratinocytes to produce IL-6 and TNF-alpha. These naRNA-LL-37 complexes also triggered neutrophil activation, creating a self-amplifying loop: activated neutrophils release NETs containing LL-37, the LL-37 binds released RNA, the complexes activate more neutrophils and keratinocytes, which recruit additional neutrophils.^[4]

This autocrine/paracrine loop explains why psoriatic inflammation is so difficult to resolve once established. The neutrophils that are recruited to clear the initial trigger become the source of ongoing inflammatory signals.

How LL-37 Activates Dendritic Cells

Dendritic cells (DCs) are the immune system's primary antigen-presenting cells, responsible for initiating adaptive immune responses. LL-37 activates dendritic cells through mechanisms that depend on the type of DC and the molecular context.

Plasmacytoid Dendritic Cells (pDCs)

Plasmacytoid dendritic cells are specialized producers of type I interferons (IFN-alpha and IFN-beta). Under normal conditions, self-DNA and self-RNA released from dying cells do not activate pDCs because they cannot access the endosomal Toll-like receptors (TLR7 and TLR9) where nucleic acid sensing occurs. LL-37 changes this.

LL-37 binds to extracellular self-DNA through electrostatic interactions, forming condensed complexes that are actively endocytosed by pDCs. Once inside the endosome, the DNA accesses TLR9 and triggers IFN-alpha production. The same mechanism operates with self-RNA through TLR7.^[4] Pahar et al. (2020) reviewed how this pathway drives type I interferon production in both psoriasis and systemic lupus erythematosus, where LL-37-DNA complexes act as autoantigens.^[5]

Fuentes-Duculan et al. (2017) demonstrated that in active psoriatic lesions, LL-37 protein colocalizes with ADAMTSL5 in keratinocytes and is found in proximity to dendritic cells and other leukocytes. This spatial relationship confirms that LL-37 released from keratinocytes directly engages nearby dendritic cells in the inflamed tissue.^[6]

Myeloid Dendritic Cells (mDCs)

Myeloid dendritic cells respond to LL-37-RNA complexes through TLR8 rather than TLR7. This activation produces a different cytokine profile: TNF-alpha and IL-6 rather than type I interferons. The mDC response drives maturation into professional antigen-presenting cells capable of activating T helper cells, particularly Th1 and Th17 subsets.

LL-37 as a Direct DC Modulator

Independent of nucleic acid complexes, LL-37 can directly modify dendritic cell behavior. It increases the endocytic capacity of monocyte-derived DCs, alters expression of phagocytic receptors, and shifts cytokine production toward a Th1-promoting profile. These effects position LL-37 as a bridge between innate detection of tissue damage and the subsequent adaptive immune response.

The Interferon Connection

LL-37's ability to activate interferon production through dendritic cells has implications beyond autoimmunity. Zhang et al. (2016) showed that LL-37 and MAVS (mitochondrial antiviral signaling protein) cooperate to drive IFN-beta production in epidermal keratinocytes during skin injury. This pathway provides rapid antiviral defense at wound sites, where the skin barrier is compromised and viral entry is a risk.^[7]

Lu et al. (2017) found elevated LL-37 levels in patients with polymyositis and dermatomyositis, two autoimmune muscle diseases characterized by type I interferon signatures. LL-37 co-localized with inflammatory infiltrates in muscle tissue and correlated with interferon-stimulated gene expression, suggesting it amplifies the interferon cascade in these conditions.^[8]

The interferon connection links Vitamin D and LL-37: Why Sunlight Boosts Your Antimicrobial Peptides to autoimmune disease through a chain: vitamin D increases LL-37, LL-37 can complex with self-nucleic acids, and these complexes activate interferon production in dendritic cells. Whether increased vitamin D (and thus increased LL-37) would worsen or improve autoimmune conditions likely depends on the tissue context and baseline inflammatory state.

LL-37 and T Cell Polarization

LL-37 does not stop at innate immune cell activation. It influences how dendritic cells instruct T helper cell differentiation, with consequences for adaptive immunity.

Thomi et al. (2018) measured elevated LL-37 in hidradenitis suppurativa lesions and found it associated with a Th1/Th17 immune response profile. The Th17 component is relevant because IL-17-producing T cells drive neutrophil recruitment, creating a positive feedback loop: LL-37 activates DCs, DCs promote Th17 differentiation, Th17 cells produce IL-17 that recruits more neutrophils, and those neutrophils release more LL-37.^[9]

Altieri et al. (2025) added a new dimension to this picture. They showed that LL-37 modulates IL-17A/F-mediated responses in bronchial epithelial cells, selectively suppressing lipocalin-2 production. Citrullinated LL-37, a modified form produced during NETosis when peptidylarginine deiminases convert arginine residues to citrulline, had different immunomodulatory effects than native LL-37. This citrullination changes the peptide's charge and structure, altering which receptors it engages and which downstream pathways it activates.^[10]

The existence of citrullinated LL-37 as a distinct immunomodulatory species means that NETosis does not simply release LL-37. It generates a modified version with different biological properties, adding another regulatory layer to the neutrophil-dendritic cell-T cell axis.

Cathelicidin in the Central Nervous System

The immune-activating properties of LL-37 extend beyond peripheral tissues. Verma et al. (2024) investigated cathelicidin expression in the central nervous system in the context of multiple sclerosis. They found that cathelicidin expression in neutrophils promoted neuroinflammation, consistent with its known immune-activating effects. However, cathelicidin expressed by neurons had the opposite effect, suppressing neuroinflammation.^[11]

This cell-type-specific duality is striking. The same peptide, produced by different cell types in the same tissue, drives opposite inflammatory outcomes. In neutrophils, cathelicidin activates neighboring immune cells and amplifies inflammation. In neurons, it appears to engage anti-inflammatory pathways that limit immune-mediated damage. The receptors and co-factors available in each cell type likely determine these divergent effects.

What Remains Unresolved

Several aspects of LL-37's immune cell activation remain incomplete:

Concentration thresholds for each receptor and each cell type have not been systematically mapped in human tissues. Most studies use recombinant LL-37 at defined concentrations in vitro, but the actual concentrations at inflammatory sites in vivo are poorly characterized.

Citrullination kinetics during NETosis are not well defined. How quickly LL-37 is citrullinated after release, what fraction remains in its native form, and whether citrullinated LL-37 has antimicrobial activity comparable to the native peptide are open questions.

Cross-talk between receptors is likely important but understudied. LL-37 engages at least six receptors on immune cells, and most studies examine one receptor at a time. How simultaneous signaling through FPRL1, P2X7, CXCR2, and TLR pathways is integrated within a single neutrophil or dendritic cell is not known.

Temporal dynamics of LL-37's effects on immune cell populations remain poorly mapped. Most in vitro studies assess fixed time points (typically 4-24 hours), but immune responses in vivo unfold over days. Whether LL-37's neutrophil survival effects persist beyond 48 hours, how quickly dendritic cell activation translates into T cell priming, and whether repeated LL-37 exposure leads to receptor desensitization are all clinically relevant questions without clear answers.

Tissue-specific responses complicate translation from in vitro to in vivo. The Verma et al. (2024) finding that cathelicidin has opposite effects in neutrophils versus neurons demonstrates that cell-type context matters enormously.^[11] Whether similar cell-type divergence exists in the gut mucosa, where LL-37 contacts both immune cells and epithelial cells simultaneously, remains to be determined.

The broader context of antimicrobial peptide-microbiome interactions adds another layer. See How Your Antimicrobial Peptides Shape Your Microbiome for how these peptides interact with commensal bacteria, and Antimicrobial Peptides as Alternatives to Antibiotics: Can They Solve Resistance? for the therapeutic implications.

The Bottom Line

LL-37 coordinates innate immune responses by recruiting neutrophils through FPRL1, extending their survival via Bcl-XL upregulation, and activating dendritic cells through nucleic acid complexes that engage TLR7, TLR8, and TLR9. These pathways bridge innate and adaptive immunity by promoting Th1/Th17 T cell polarization. The same mechanisms that provide antimicrobial defense can drive autoimmune pathology when LL-37 complexes with self-nucleic acids in conditions like psoriasis and lupus.

Frequently Asked Questions

How does LL-37 attract neutrophils to infection sites?

LL-37 acts as a chemoattractant by binding the formyl peptide receptor-like 1 (FPRL1/FPR2) on neutrophil surfaces. This triggers intracellular calcium mobilization and directed cell migration toward the LL-37 source. Scott et al. (2002) showed this works at nanomolar concentrations, well below the levels needed for direct bacterial killing, meaning LL-37 functions as a recruitment signal before reaching antimicrobial concentrations.

Does LL-37 keep neutrophils alive longer?

Yes. LL-37 extends neutrophil lifespan by upregulating the anti-apoptotic protein Bcl-XL and downregulating the pro-apoptotic protein Bid, primarily through FPRL1 and P2X7 receptor signaling (Bucki et al., 2010). This delays the normal 24-hour neutrophil self-destruct program. Extended survival enhances pathogen clearance during acute infection but can perpetuate tissue damage in chronic inflammatory conditions.

How does LL-37 activate dendritic cells?

LL-37 binds to extracellular self-DNA and self-RNA through electrostatic interactions, forming condensed complexes that are endocytosed by dendritic cells. Inside endosomes, DNA activates TLR9 in plasmacytoid dendritic cells (producing type I interferons), while RNA activates TLR7 in plasmacytoid DCs and TLR8 in myeloid DCs (producing TNF-alpha and IL-6). This converts normally inert self-nucleic acids into immune-activating signals.

What are neutrophil extracellular traps and how does LL-37 contribute?

Neutrophil extracellular traps (NETs) are web-like structures of chromatin and antimicrobial proteins released by dying neutrophils to trap bacteria. LL-37 is embedded in NETs and binds to NET-associated RNA, forming complexes that activate keratinocytes and additional neutrophils. Herster et al. (2020) showed this creates a self-amplifying inflammatory loop, particularly relevant in psoriasis.

What is citrullinated LL-37?

Citrullinated LL-37 is a modified form produced during NETosis when enzymes called peptidylarginine deiminases convert arginine residues to citrulline. This changes the peptide's charge and three-dimensional structure, altering which receptors it engages. Altieri et al. (2025) showed that citrullinated LL-37 modulates IL-17 responses differently than native LL-37, meaning NETosis generates a functionally distinct immunomodulatory species.

Does LL-37 affect T cell responses?

Indirectly, yes. By activating dendritic cells to produce specific cytokine profiles, LL-37 promotes Th1 and Th17 T cell differentiation. Th17 cells produce IL-17, which recruits more neutrophils, creating a positive feedback loop. This is relevant in hidradenitis suppurativa (Thomi et al., 2018) and airway inflammation (Altieri et al., 2025), where LL-37-driven Th17 responses amplify neutrophilic inflammation.