What Is IL-34 and Its Role in Disease?

Interleukin-34, or IL-34, is a signaling protein discovered in 2008 that acts as a growth factor for certain immune cells, particularly macrophages and their relatives throughout the body. It was found through a screening approach designed to identify new molecules that could activate a well-known immune receptor called CSF-1R, and its discovery immediately raised questions because another molecule, CSF-1, was already known to do that job.¹ Since then, IL-34 has turned up in an unexpectedly wide range of diseases, from rheumatoid arthritis and lupus to cancer and liver fibrosis, making it one of the more intriguing immune molecules to emerge in recent years.

A Second Key to the Same Lock

The immune system relies on receptors sitting on cell surfaces that respond when specific signaling molecules bind to them. For decades, CSF-1 (also called M-CSF) was considered the sole activator of the CSF-1 receptor, which governs the survival, growth, and activity of macrophages and related cells. IL-34 upended that picture. Despite sharing no meaningful structural resemblance to CSF-1, it binds the same receptor and triggers many of the same downstream effects, including cell proliferation, differentiation, and migration.²

The two molecules are not simply interchangeable backups, though. They are produced in different tissues and at different times during development. CSF-1 is expressed broadly across many organs, whereas IL-34 is concentrated in specific niches like the brain and skin. This spatial separation means the body can fine-tune macrophage behavior in particular tissues without affecting macrophages elsewhere.³

IL-34 Has Its Own Receptor Portfolio

While the CSF-1 receptor is the best-studied partner for IL-34, research over the past decade has revealed that IL-34 also binds to at least three additional receptors that CSF-1 does not use. These include PTP-ζ (a receptor phosphatase found heavily in the brain), syndecan-1 (a surface molecule on many cell types), and TREM2 (an immune receptor linked to neurodegeneration research).⁴ The interaction with PTP-ζ is especially interesting because it gives IL-34 a direct line into brain biology that CSF-1 lacks. Syndecan-1, meanwhile, can modulate how strongly IL-34 activates its primary receptor, essentially turning the volume up or down on signaling at the cell surface.⁵

This multi-receptor capability helps explain why IL-34 pops up in so many different disease contexts. It is not restricted to one signaling channel; it can influence immune cells, nerve cells, and connective tissue cells through different doorways depending on which receptors those cells carry.

What IL-34 Does Under Normal Conditions

In healthy tissues, IL-34 plays housekeeping roles that are difficult to replace. Two cell populations depend on it most critically: microglia in the brain and Langerhans cells in the skin.

Microglia are the brain’s resident immune cells. They survey the neural environment, clear debris, prune unnecessary connections during development, and respond to injury. Studies in mice lacking IL-34 showed that microglia develop from yolk-sac precursors independently of the molecule, but once the brain matures, they need IL-34 to persist. Without it, microglia numbers drop substantially in the adult brain, while other macrophage populations throughout the body remain unaffected.⁶

Langerhans cells are immune sentinels that live in the outer layer of the skin. Keratinocytes, the cells that form the skin’s barrier, produce IL-34 to support Langerhans cell survival. During embryonic development, IL-34 drives the final maturation step for Langerhans cell precursors, and throughout adult life the cells continue to depend on it for routine self-renewal.⁷ Lose IL-34, and the skin’s immune surveillance weakens.

The Bone Connection

Bone is a constantly remodeling tissue. Old bone is broken down by osteoclasts, large cells formed from the fusion of immune precursors, and new bone is laid down by osteoblasts. For years, CSF-1 was thought to be the essential growth factor that, together with RANKL, drives osteoclast formation. IL-34 can substitute entirely. In lab models, IL-34 combined with RANKL produces fully functional, bone-resorbing osteoclasts, and the effect is dose-dependent: more IL-34 yields more osteoclasts and larger resorption pits.⁸ This finding has particular relevance in bone tumors. Giant cell tumors of bone, for instance, express IL-34, which contributes to the aggressive bone destruction these tumors cause.⁹

Rheumatoid Arthritis

Rheumatoid arthritis (RA) involves chronic inflammation of the joint lining, and IL-34 appears woven into that process at multiple levels. In RA patients, IL-34 is detectable in the vast majority of synovial biopsies, and its expression correlates with how severe the synovitis is.¹⁰ IL-34 levels tend to be higher in joint fluid than in the bloodstream, suggesting the cytokine concentrates where the damage is happening.¹¹

The mechanism appears to work as a vicious loop. Inflammatory signals like TNF-alpha push the fibroblast-like cells in the joint lining to produce IL-34 preferentially over CSF-1. That IL-34 then attracts immune cells into the joint and promotes osteoclast formation, contributing to the bone erosion characteristic of RA. Encouragingly, when patients receive disease-modifying drugs, their circulating IL-34 levels drop in parallel with clinical improvement, hinting that IL-34 could serve as a treatment-response marker.¹²

Lupus and Kidney Involvement

Systemic lupus erythematosus (SLE) is an autoimmune disease where the immune system attacks the body’s own tissues, often including the kidneys. Circulating IL-34 levels are markedly elevated in people with SLE compared with healthy individuals. In one study focused on juvenile lupus patients, the average IL-34 concentration was roughly five times higher than in controls, and the highest readings were found in patients with active disease and kidney involvement.¹³ A separate study in adult SLE patients found IL-34 detectable in about seven out of ten SLE patients but in fewer than one in ten healthy controls.¹⁴

In animal models of lupus nephritis, IL-34 produced by kidney tubular cells appears to amplify local inflammation. The expression patterns seen in these mouse models closely mirror what is found in human lupus kidneys, and IL-34 expression in kidney tissue correlates with disease activity.¹⁵ This suggests IL-34 is not simply a bystander but an active participant in the kidney damage that makes lupus so dangerous.

Inflammatory Bowel Disease

Both Crohn’s disease and ulcerative colitis show elevated IL-34 in inflamed gut tissue. The cytokine is produced by intestinal lining cells and by immune cells that infiltrate the gut wall, and its expression rises significantly in inflamed areas compared with uninvolved tissue from the same patients or tissue from healthy controls.¹⁶ TNF-alpha, the inflammatory signal that many IBD drugs target, is one of the main drivers of IL-34 production in the gut. In a telling experiment, treating IBD tissue samples with infliximab, a TNF-blocking antibody, brought IL-34 levels down. Conversely, adding IL-34 to gut immune cells boosted their production of TNF-alpha, creating a self-reinforcing inflammatory circuit.¹⁷

Beyond inflammation, IL-34 may also contribute to the fibrosis, or tissue scarring, that complicates Crohn’s disease. When gut fibroblasts are exposed to IL-34, they ramp up collagen production. In fibroblasts already taken from fibrotic Crohn’s tissue, knocking down IL-34 reduces their collagen output.¹⁸ So IL-34 may be doing double damage in IBD: feeding the inflammatory fire and worsening the structural scarring that follows.

Cancer and the Tumor Microenvironment

The relationship between IL-34 and cancer is a story about immune evasion. Tumors need to avoid being destroyed by the immune system, and one of their most effective strategies is reprogramming the macrophages that surround them. Rather than attacking tumor cells, these “tumor-associated macrophages” (TAMs) can be co-opted into suppressing the immune response and even helping the tumor survive treatment.

IL-34 plays a direct role in this co-option. In lung cancer, chemotherapy itself triggers cancer cells to produce more IL-34, which then pushes nearby macrophages toward an immunosuppressive state and helps chemotherapy-resistant cancer cells survive.¹⁹ A 2024 study shed further light on the mechanism: when tumors lose the tumor-suppressor gene p53, IL-34 production surges, reprogramming macrophages into a fat-laden, immunosuppressive form that actively blocks the killer T cells that would otherwise attack the tumor.²⁰

This has direct therapeutic implications. Immune checkpoint therapies like anti-PD-1 antibodies work by releasing the brakes on T cells so they can attack tumors, but if IL-34-reprogrammed macrophages are suppressing those T cells at the tumor site, checkpoint therapy alone may not be enough. In mouse models, combining PD-1 blockade with an antibody that neutralizes IL-34 significantly improved tumor shrinkage compared with PD-1 blockade alone.²¹ These are animal results, not clinical trials in humans, but they suggest that blocking IL-34 could be a way to enhance the effectiveness of immunotherapy.

Liver Fibrosis and Viral Hepatitis

Chronic liver disease from hepatitis B or C infection often progresses to fibrosis, where scar tissue gradually replaces healthy liver. IL-34 appears to accelerate this process. In hepatitis C-related fibrosis, IL-34 drives macrophages toward a pro-fibrotic state that stimulates hepatic stellate cells, the main collagen-producing cells in the liver, to churn out scar tissue.²²

In chronic hepatitis B, blood IL-34 levels track with the degree of liver inflammation and fibrosis stage. Researchers found that a serum IL-34 cutoff could identify severe fibrosis with high sensitivity and specificity, raising the possibility that a simple blood test for IL-34 could reduce the need for liver biopsies in some patients.²³ Intriguingly, IL-34 does not only promote fibrosis; in lab and animal experiments, it also directly inhibits hepatitis B virus replication, reducing viral DNA and protein levels in both cell cultures and transgenic mice.²⁴ So IL-34 may have a dual personality in hepatitis B: fighting the virus while simultaneously worsening the tissue damage the infection leaves behind.

Alzheimer’s Disease and Neuroprotection

Given that IL-34 is the primary survival factor for microglia in the adult brain, researchers have explored whether it could be leveraged against neurodegenerative diseases. In Alzheimer’s disease, toxic clumps of amyloid-beta protein accumulate and damage neurons. In cell culture and in a mouse model of Alzheimer’s, IL-34 enhanced the ability of microglia to clear soluble amyloid-beta. It boosted production of an enzyme that degrades amyloid and induced an antioxidant enzyme that reduces oxidative damage, all without triggering the kind of neurotoxic inflammation that can make microglial activation harmful. Mice that received IL-34 directly into the brain showed improved associative learning and lower amyloid levels.²⁵

These findings are promising but early-stage. The brain delivery challenge alone is formidable, and what works in transgenic mouse models of Alzheimer’s has a poor track record of translating to humans. Still, IL-34’s unique position as a microglial survival signal that can push microglia toward protective rather than destructive behavior makes it an appealing candidate for further study.

Obesity, Insulin Resistance, and Heart Disease

IL-34 levels are not confined to traditionally “immune” diseases. People with obesity have significantly higher circulating IL-34 regardless of whether they also have diabetes, and IL-34 concentrations correlate positively with markers of insulin resistance. The protein is expressed in fat tissue, particularly the visceral fat around internal organs, and its production increases during fat cell development. In cell experiments, IL-34 promoted fat accumulation and blunted the ability of insulin to stimulate glucose uptake. After bariatric surgery and the resulting weight loss, serum IL-34 dropped significantly.²⁶

In cardiovascular disease, IL-34 has been linked to atherosclerosis, the buildup of fatty plaques in arteries. Researchers have characterized it as pro-atherogenic and associated with unstable plaques, the kind most likely to rupture and cause heart attacks.²⁷ In patients with ischemic cardiomyopathy, serum IL-34 levels are elevated compared with controls, and higher IL-34 tracks with worse heart failure as measured by standard clinical indicators. Statistical analysis showed that IL-34 was independently associated with the presence and severity of ischemic heart failure even after adjusting for conventional risk factors.²⁸

IL-34 as a Biomarker

The pattern across these diseases is striking: wherever researchers measure IL-34, elevated levels tend to correlate with disease severity, active inflammation, or worse outcomes. That consistency makes IL-34 an attractive candidate as a blood biomarker. In RA, levels fall when treatment works. In lupus, they rise with kidney involvement. In chronic hepatitis B, they can flag severe fibrosis. In heart failure, they track with functional class.²⁹

A biomarker is only useful, though, if it tells you something you cannot already learn from existing tests. IL-34 is not yet part of routine clinical practice. Most of the associations come from single-center studies with modest sample sizes, and no large prospective trial has validated IL-34 as superior to established markers in any disease. The hepatitis B fibrosis data is among the more developed, where a serum IL-34 threshold showed sensitivity above 85% and specificity near 80% for identifying advanced fibrosis, but even there the findings need replication in larger, more diverse populations.²³

Pregnancy and Immune Tolerance

One of immunology’s great puzzles is how a pregnant person’s immune system avoids attacking the fetus, which is genetically half foreign. The fetal-maternal interface turns out to be another site where IL-34 does meaningful work. Both placental cells and decidual stromal cells in the uterine lining produce IL-34. When blood monocytes are exposed to IL-34 in the lab, they transform into macrophages with a profile closely resembling the regulatory macrophages naturally found in the decidua, the immune-dampening cells that help maintain tolerance toward the fetus.³⁰ This suggests IL-34 contributes to the carefully calibrated immune suppression needed for successful pregnancy, though whether abnormal IL-34 levels play a role in complications like recurrent miscarriage or preeclampsia remains an open question.

Therapeutic Angles and Open Questions

Because IL-34 feeds into so many disease processes, blocking it is an obvious therapeutic idea, and the cancer immunotherapy data already mentioned is one example of that approach showing early promise in animal models.²¹ Drugs that block the CSF-1 receptor already exist and are in clinical trials for various cancers, but these drugs hit both CSF-1 and IL-34 signaling simultaneously. Selectively targeting IL-34 while leaving CSF-1 alone could, in theory, dampen harmful inflammation in specific tissues without wiping out macrophage populations everywhere. The existence of IL-34-specific receptors like PTP-ζ and TREM2 adds another layer: drugs aimed at those interactions could influence brain or connective tissue biology without broadly suppressing the immune system.

On the flip side, in conditions like Alzheimer’s disease, delivering more IL-34 might be beneficial rather than harmful, because it could support the protective functions of microglia. That tension, where IL-34 is a driver of pathology in one organ and a potential therapy in another, is the central challenge of translating IL-34 biology into medicine. Any future treatment will need to be carefully targeted by disease context, tissue, and timing. For now, IL-34 sits in a space that is typical of many cytokines: rich with preclinical promise, thin on clinical proof, and full of the kind of biological complexity that makes simple answers unlikely.