LL-37

What it is

LL-37 consists of 37 amino acids and is the only human cathelicidin. Other animals have whole families of them; we have exactly 1. It is found in neutrophil granulocytes, the phagocytes that are first to arrive at an infection, and is released where it is needed.

There is a clean link to a better-known topic: the vitamin D receptor switches on the gene from which LL-37 is made. Vitamin D thus sits upstream of this peptide in the signaling chain. This is a genuine connection and one of the reasons why immune function comes up at all in discussions of vitamin D.

How it works

LL-37 performs 3 tasks. First, it kills germs by tearing open their membrane, and this affects bacteria, fungi and enveloped viruses. It is a hole-in-the-wall mechanism against which resistance hardly develops. Second, it calls for reinforcements by attracting more immune cells to the site. Third, it helps with wound healing by promoting the migration of skin cells and the formation of new blood vessels.

The decisive factor here is regulation. In the body, LL-37 is released in the right place, in the right amount and for a short time. It is precisely this rule that makes the substance useful.

What has been tested in humans

Studies in humans do exist, and that is remarkable. They are just usually cited incorrectly. They are studies on open wounds, and LL-37 was applied to the wound, not injected.

In 2014 there was a smaller study on poorly healing leg ulcers with a positive result. A larger one followed: 148 patients, several centers, blinded, placebo-controlled, 2 concentrations, 13 weeks. In the overall group there was no significant benefit; the primary endpoint was not met. A second study in diabetic foot wounds found better tissue regeneration, also as a cream.

The other face

LL-37 is not only a weapon of the immune system. It is also one of the targets the immune system can turn against. In psoriasis it is a recognized autoantigen. The mechanism is well described: LL-37 binds to the body’s own DNA, and this complex awakens certain immune cells via a receptor that is actually responsible for the genetic material of pathogens. What follows is an interferon response, and that stands at the beginning of psoriasis.

In rosacea it is similar, only the other way around: there, too much of an enzyme is at work that cuts LL-37 incorrectly, and these fragments are more pro-inflammatory than the intact molecule. Anyone who has rosacea and takes LL-37 may be giving the disease more raw material.

What the studies show

Leg ulcers — the smaller study from 2014

A smaller study on poorly healing leg ulcers, with LL-37 applied to the wound, reached a positive result in 2014. It was the reason for the larger program.

Leg ulcers — the larger study

148 patients, several centers, blinded, placebo-controlled, 2 concentrations, 13 weeks. In the overall group there was no significant benefit; the primary endpoint was not met. In the subgroup with particularly large wounds, 10 square centimeters or more, 28 percent of wounds closed completely versus 8 percent on placebo. That is a signal, not a result: it is plausible that a wound-healing agent achieves more where there is more to heal, but it remains an analysis after the primary finding.

Diabetic foot wounds

A second study in diabetic foot wounds found better tissue regeneration. Here, too, LL-37 was applied topically, as a cream.

What the wound studies do not show

There are no data on injected LL-37 in healthy people: no approval, no long-term safety data. The only injection study in humans, a phase I study with administration directly into skin metastases in melanoma, does not answer this question. Everything reliably known comes from application to wounds. What is advertised, by contrast, is the injection, against persistent infections, against biofilms, against everything chronic where antibiotics no longer help. That is a double leap: from wound dressing to injection, and from a wound on the leg to the whole body.

The subgroup with the large wounds does not support this leap either. It is an analysis after the primary finding, and the primary finding was negative. As far as the advertised use is concerned, the data are therefore empty.

Status, approval and legal

There is no approval for injection. What is traded in the scene is accordingly not a tested preparation, but product without approval and without safety data for this route of administration. LL-37 is being developed further where it has been studied: topically, for poorly healing wounds.

Safety

The mechanism itself is the warning. LL-37 punches holes in membranes, and this selectivity is not perfect: at higher concentrations it also attacks human cells. In the body this is not a problem, because release is strictly regulated, in the right place, in the right amount, for a short time. An injection overrides both, and nobody knows at what concentration the substance ends up where. Added to this is the autoimmune side: in psoriasis LL-37 is a recognized autoantigen, and in rosacea incorrectly cut fragments provide additional inflammatory stimulus. Anyone with an autoimmune disease, especially psoriasis or lupus, should steer clear of this substance; that is not caution on suspicion but the described mechanism. The effect on tumors has also been described as tissue-dependent, growth-promoting in some contexts and inhibitory in others. That is no proof of danger, but it fits a substance that promotes the formation of new blood vessels.

Sources

• Grönberg et al., Wound Repair Regen 2014 (smaller study on poorly healing leg ulcers)
• Mahlapuu et al., Wound Repair Regen 2021 (blinded, placebo-controlled study on leg ulcers, 148 patients, 13 weeks)
• Miranda et al., Arch Dermatol Res 2023 (study on diabetic foot wounds, topical application)
• Lande et al., Nat Commun 2014 (LL-37 as an autoantigen in psoriasis)
• Yamasaki et al., Nat Med 2007 (rosacea and enzymatic cleavage of LL-37)
• Dolkar et al., J Cutan Pathol 2018 (case report from the phase I study: 8 weekly injections into melanoma skin metastases, skin side effects)