LL-37's Dual Role: Anti- and Pro-Inflammatory

LL-37

Dual role

LL-37 simultaneously suppresses systemic endotoxin responses and amplifies local immune cell recruitment, a paradox central to cathelicidin biology.

Pinheiro da Silva & Machado, Immunology Letters, 2017

Pinheiro da Silva & Machado, Immunology Letters, 2017

View as image

A peptide that fights inflammation and causes inflammation at the same time sounds like a contradiction. For LL-37, it is the central feature of its biology. As the pillar article on LL-37: The Immune Peptide That Does Everything describes, this peptide operates across antimicrobial, wound healing, and immunomodulatory domains. The question driving this article is specific: how does the same 37-amino-acid peptide suppress inflammatory signaling in one context while amplifying it in another?

Pinheiro da Silva and Machado (2017) framed this as cathelicidin's "dual role" in systemic inflammation. Their review established that cathelicidins dampen excessive inflammatory responses in the bloodstream (protective during sepsis) while simultaneously recruiting and activating immune cells at local tissue sites (protective against focal infection). The balance between these effects determines clinical outcomes.^[1]

The Anti-Inflammatory Side

Endotoxin Neutralization

LL-37's most established anti-inflammatory function is endotoxin neutralization. LPS (lipopolysaccharide), a component of Gram-negative bacterial cell walls, is one of the most potent triggers of systemic inflammation. When LPS binds TLR4 on macrophages, it activates NF-kB signaling, producing a cytokine storm of TNF-alpha, IL-1-beta, and IL-6 that, unchecked, leads to septic shock and organ failure.

LL-37 binds LPS directly through electrostatic interactions between its cationic residues and the negatively charged lipid A moiety of LPS. This binding prevents LPS from engaging TLR4/MD-2 on macrophage surfaces, effectively neutralizing the endotoxin before it can trigger inflammatory signaling.^[2]

Scott et al. (2002) demonstrated that LL-37 suppresses macrophage activation by LPS, lipoteichoic acid (from Gram-positive bacteria), and noncapped lipoarabinomannan (from mycobacteria). The suppression extended to both TNF-alpha and nitric oxide production, the two primary effector molecules of macrophage inflammatory responses.^[2]

Anti-Inflammatory Cytokine Induction

Beyond blocking pro-inflammatory signals, LL-37 actively promotes anti-inflammatory mediator production. In monocytes and macrophages, LL-37 can upregulate IL-10, a cytokine that suppresses inflammatory cascades and promotes tissue repair. Bucki et al. (2010) reviewed the evidence showing that LL-37's immunomodulatory effects include both direct suppression of pro-inflammatory cytokines and indirect promotion of anti-inflammatory pathways.^[3]

The anti-inflammatory cytokine induction is receptor-dependent. LL-37 engages with intracellular signaling cascades that alter TLR-to-NF-kB pathways, reducing the transcription of pro-inflammatory genes even in the continued presence of bacterial components. This is not simply competitive inhibition of LPS binding: LL-37 reprograms the macrophage response at the transcriptional level, shifting it from a pro-inflammatory (M1) toward a resolution-oriented (M2) phenotype. This reprogramming persists for hours after LL-37 exposure, suggesting it represents a genuine shift in macrophage polarization rather than a transient blockade.

Protection in the Gut

The gastrointestinal tract provides one of the clearest examples of LL-37's anti-inflammatory function in a disease context. Gubatan et al. (2020) demonstrated that cathelicidin mediates a protective role for vitamin D in ulcerative colitis. In human colonic epithelial cells, vitamin D-induced cathelicidin expression reduced inflammatory signaling and enhanced barrier function. In UC patients, serum cathelicidin levels correlated with clinical remission, suggesting the peptide serves as both an effector and a biomarker of the anti-inflammatory vitamin D pathway.^[4]

Wu et al. (2010) reviewed cathelicidin's broader therapeutic potential across GI disorders. In peptic ulcer disease, cathelicidin expression increases in response to Helicobacter pylori infection, and the peptide both kills bacteria and modulates the mucosal immune response to prevent excessive inflammation that would damage the gastric lining.^[5]

The Pro-Inflammatory Side

Immune Cell Recruitment

LL-37 is chemotactic for neutrophils, monocytes, and T cells through FPRL1 (formyl peptide receptor-like 1). This recruitment function amplifies the local immune response by drawing effector cells to infection or injury sites. The chemotactic activity occurs at nanomolar concentrations, lower than the micromolar levels needed for direct antimicrobial killing.^[2]

For a detailed examination of how LL-37 activates each immune cell type, see How LL-37 Activates Neutrophils and Dendritic Cells.

Inflammasome Activation

In skin, LL-37 activates the NLRP3 inflammasome, a multiprotein complex that processes pro-IL-1-beta and pro-IL-18 into their active, pro-inflammatory forms. Yoon et al. (2021) showed that LL-37 drives rosacea-like skin inflammation through this NLRP3 pathway. In their mouse model, LL-37 injection produced erythema, pustules, and immune cell infiltration that was significantly reduced in NLRP3-deficient mice.^[6]

NLRP3 activation by LL-37 connects the innate antimicrobial response to the adaptive immune system. IL-1-beta produced by the inflammasome promotes Th17 differentiation, which in turn drives neutrophil recruitment through IL-17-mediated chemokine production. This creates the positive feedback loop characteristic of chronic inflammatory skin conditions like rosacea and hidradenitis suppurativa.

Dendritic Cell Activation and Interferon Production

LL-37's pro-inflammatory effects reach their extreme in autoimmune contexts. When LL-37 complexes with self-DNA or self-RNA released from dying cells, these complexes activate plasmacytoid dendritic cells through TLR9 (for DNA) and TLR7 (for RNA), triggering type I interferon production. Pahar et al. (2020) reviewed this mechanism in psoriasis and systemic lupus erythematosus, where LL-37-nucleic acid complexes function as autoantigens that perpetuate chronic inflammation.^[7]

Herster et al. (2020) refined this model by showing that NET-associated RNA, not DNA, is the primary driver of the LL-37-dependent inflammatory amplification loop in psoriasis. LL-37-RNA complexes activated keratinocytes to produce IL-6 and TNF-alpha, which recruited additional neutrophils that released more NETs, perpetuating the cycle.^[8]

What Determines Which Role Dominates?

Three factors appear to determine whether LL-37's anti-inflammatory or pro-inflammatory effects prevail in a given context:

Concentration

At low concentrations (nanomolar range), LL-37 primarily functions as a chemoattractant and immune modulator. At higher concentrations (micromolar range), direct antimicrobial killing and cytotoxicity to host cells become dominant. The inverted dose-response curve seen in the Gronberg et al. (2014) wound healing trial, where 0.5 mg/mL outperformed 1.6 and 3.2 mg/mL, illustrates this concentration dependence in a clinical setting.^[9]

Tissue Context

In the bloodstream, where LPS neutralization is the primary need, LL-37's anti-inflammatory effects dominate. In skin and mucosal surfaces, where local immune activation against invading pathogens is critical, pro-inflammatory effects take precedence. The receptor repertoire available on resident cells differs between tissues, which shapes which downstream pathways LL-37 engages.

Fabisiak et al. (2016) reviewed how LL-37's effects vary across four major systems: immunological, respiratory, gastrointestinal, and dermatological. In each system, the balance between pro- and anti-inflammatory outcomes differs based on the local cellular environment and the presence or absence of co-stimulatory signals.^[10]

Presence of Self-Nucleic Acids

The transformation from anti-inflammatory to pro-inflammatory is most dramatic when LL-37 encounters self-DNA or self-RNA from dying cells. In the absence of self-nucleic acids, LL-37 tends toward anti-inflammatory endotoxin neutralization and wound healing. In their presence (as occurs in psoriatic plaques, lupus flares, and chronic wounds with extensive cell death), LL-37 drives autoimmune activation through dendritic cell stimulation.

This nucleic acid dependency creates a threshold effect: below a certain level of cell death, LL-37 is healing; above it, LL-37 becomes destructive.

Receptor Co-expression

The receptors through which LL-37 signals differ across cell types and activation states. Resting monocytes express different levels of FPRL1, P2X7, and TLR9 than activated macrophages or immature dendritic cells. The receptor landscape on a given cell determines which of LL-37's many functions dominate. A neutrophil arriving at an infected wound responds to LL-37 primarily through FPRL1 (chemotaxis) and P2X7 (survival signaling). A plasmacytoid dendritic cell in a psoriatic plaque responds primarily through endosomal TLR7/9 (interferon production). The peptide is the same; the cellular context produces opposite outcomes.

This receptor-dependent model also explains why LL-37's effects can shift over the time course of an immune response. Early in infection, when the tissue contains mostly resting resident cells, anti-inflammatory endotoxin neutralization predominates. As immune cells are recruited and activated, the receptor landscape changes, and pro-inflammatory signaling pathways become accessible.

Separating the Two Roles

One approach to resolving the dual-role problem is to identify cathelicidin variants that exhibit only one function. Luo et al. (2021) characterized TK-CATH, the first anionic cathelicidin identified in nature, from the salamander Tylototriton kweichowensis. Unlike LL-37 (which carries a net charge of +6), TK-CATH carries a net charge of -3. It showed no direct antimicrobial activity but possessed potent anti-inflammatory effects, inhibiting LPS-induced TNF-alpha, IL-6, and nitric oxide production in macrophages through MAPK pathway suppression. It also promoted wound healing by inducing cell migration and growth factor production.^[11]

The existence of a naturally occurring cathelicidin with separated functions suggests that the anti-inflammatory and antimicrobial activities of cathelicidins can be decoupled. This has implications for therapeutic design: it may be possible to engineer LL-37 derivatives that retain the anti-inflammatory and wound-healing properties while eliminating the autoimmune-triggering capacity.

What This Means for Therapeutic Development

The dual-role biology creates a fundamental challenge: any intervention that increases LL-37 systemically could simultaneously protect against sepsis while worsening psoriasis or lupus. Any intervention that decreases LL-37 to treat autoimmune conditions could increase susceptibility to infection.

Current approaches to navigating this include:

Topical delivery limits LL-37 exposure to the target tissue, avoiding systemic effects. The Gronberg wound healing trial used topical application for this reason.

Modified peptides that retain specific functions while eliminating others. The TK-CATH discovery suggests this is biologically feasible. Synthetic LL-37 fragments with altered charge distributions could potentially separate antimicrobial from immunomodulatory activity.

Vitamin D modulation as an indirect approach. Since vitamin D upregulates endogenous LL-37 production, vitamin D supplementation represents a physiological way to increase cathelicidin levels. Whether this approach selectively enhances anti-inflammatory effects (as seen in UC) or also increases pro-inflammatory risk in susceptible individuals remains an open question explored in Vitamin D and LL-37: Why Sunlight Boosts Your Antimicrobial Peptides.

The dual role is not a flaw to be engineered away. In a healthy immune system, the balance between LL-37's opposing functions is precisely regulated by concentration, tissue context, and available binding partners. Disease arises when this balance is disrupted, either by excessive LL-37 in tissues with abundant self-nucleic acids (autoimmunity) or by insufficient LL-37 at mucosal surfaces (infection susceptibility). Understanding where each patient falls on this spectrum, and which of LL-37's functions is dominant in their specific disease context, will be essential for any therapeutic strategy that targets this peptide or its regulatory pathways.

The Bottom Line

LL-37 exhibits genuinely opposing inflammatory effects: it neutralizes endotoxin and suppresses macrophage activation (anti-inflammatory) while simultaneously recruiting immune cells and activating the NLRP3 inflammasome (pro-inflammatory). Which role dominates depends on concentration, tissue context, and whether self-nucleic acids are present. This duality is protective in healthy immune responses but becomes pathological in conditions like psoriasis and lupus, where LL-37-nucleic acid complexes drive chronic autoimmune inflammation.

Frequently Asked Questions

Is LL-37 anti-inflammatory or pro-inflammatory?

Both. LL-37 neutralizes bacterial endotoxin (LPS) and suppresses macrophage production of TNF-alpha and nitric oxide, which is anti-inflammatory. It simultaneously recruits neutrophils and monocytes through FPRL1, activates the NLRP3 inflammasome, and can drive type I interferon production when complexed with nucleic acids. Which effect dominates depends on concentration, tissue location, and the presence of self-DNA or self-RNA.

How does LL-37 protect against sepsis?

LL-37 binds directly to LPS (lipopolysaccharide) from Gram-negative bacteria through electrostatic interactions, preventing LPS from activating TLR4 on macrophages. Scott et al. (2002) showed this blocks the production of TNF-alpha and nitric oxide, the primary mediators of septic shock. This endotoxin-neutralizing function makes LL-37 a natural antisepsis agent that prevents excessive systemic inflammation.

Why does LL-37 worsen psoriasis?

In psoriatic skin, dying cells release self-DNA and self-RNA. LL-37 binds these nucleic acids, forming complexes that are taken up by plasmacytoid dendritic cells. Inside the endosome, DNA activates TLR9 and RNA activates TLR7, triggering type I interferon production. Herster et al. (2020) showed that NET-associated RNA-LL-37 complexes also activate keratinocytes, creating a self-amplifying inflammatory loop.

Can LL-37 be modified to remove its pro-inflammatory effects?

Research suggests this is feasible. Luo et al. (2021) identified TK-CATH, a naturally occurring anionic cathelicidin from salamanders with anti-inflammatory and wound-healing activity but no antimicrobial or pro-inflammatory function. Its negative charge (compared to LL-37's positive charge) prevents it from forming the nucleic acid complexes that drive autoimmune activation. Synthetic LL-37 derivatives with modified charge distributions are an active area of research.

Does vitamin D increase LL-37 inflammation risk?

Vitamin D upregulates LL-37 production through the CAMP gene, which could theoretically increase both anti-inflammatory and pro-inflammatory effects. In ulcerative colitis, Gubatan et al. (2020) found that vitamin D-induced cathelicidin was protective and associated with clinical remission. Whether vitamin D supplementation could worsen autoimmune conditions mediated by LL-37 (like psoriasis) in susceptible individuals has not been established in clinical trials.

What determines if LL-37 helps or harms?

Three factors: concentration (low doses recruit immune cells, high doses become cytotoxic), tissue context (bloodstream exposure favors anti-inflammatory effects, skin exposure favors pro-inflammatory), and the presence of self-nucleic acids (cell death releases DNA/RNA that LL-37 converts into autoimmune triggers). In healthy tissues with intact cells and controlled LL-37 levels, the balance favors protection.