What Are Epithelioid Cells and What Is Their Function?

Epithelioid cells are immune cells derived from macrophages that have undergone a dramatic shape change, abandoning their usual rounded, mobile form to become tightly packed, flattened cells that resemble the epithelial cells lining your skin and organs. Their primary function is building and maintaining granulomas, the organized immune structures your body creates to wall off threats it cannot easily destroy. The name “epithelioid” literally means “epithelial-like,” and this resemblance turns out to be far more than cosmetic: these cells actually borrow molecular machinery from true epithelial tissue to seal themselves together into a barrier.

How Macrophages Transform Into Epithelioid Cells

The story of an epithelioid cell begins in bone marrow, where myeloid precursor cells mature into monocytes that enter the bloodstream. When monocytes leave the blood and settle into tissues, they become macrophages, the large scavenging cells that engulf bacteria, dead cells, and debris. Under most circumstances, macrophages do their cleanup work and move on. But when they encounter something they cannot digest or destroy, a different process kicks in.

Within about 24 to 48 hours of an injury or infection, signals from the immune system begin redirecting macrophages toward a new identity. Helper T cells release chemical messengers, including tumor necrosis factor, interleukin-1, interleukin-6, and interferon-gamma, that activate macrophages at the site of trouble. Under this sustained stimulation, the macrophages enlarge, their cytoplasm becomes abundant and finely granular, and their outlines blur together until individual cells become hard to distinguish under a microscope. These are now epithelioid cells. Under light microscopy, they appear with round to oval nuclei and indistinct cell borders, looking strikingly like the epithelial cells you would find lining an organ surface.

Not all epithelioid cells look the same. In some conditions, they develop extensive rough endoplasmic reticulum, the cellular machinery used for producing and secreting proteins. These “secretory” epithelioid cells have been observed in certain experimental granulomas and at sites of intense inflammation. In other situations, such as tuberculoid leprosy and some cases of sarcoidosis, the cells look more like highly activated macrophages or take on what researchers describe as a “multivesicular” appearance, packed with small membrane-bound sacs.¹ This range of appearances suggests that the epithelioid transformation is not a single fixed endpoint but rather a spectrum shaped by whatever threat the body is responding to.

Building a Sealed Wall With Borrowed Molecular Tools

The most surprising feature of epithelioid cells is not just that they look like epithelial cells but that they actually steal a page from the epithelial playbook at the molecular level. True epithelial cells, the kind that line your gut or skin, stick to one another using a protein called E-cadherin. This protein forms a core component of adherens junctions, the molecular rivets that hold epithelial sheets together and help regulate cell signaling, the internal skeleton of the cell, and cell polarity.² E-cadherin-based adherens junctions are considered a defining feature of epithelial sheets, ensuring that neighboring cells remain firmly glued together.³

Macrophages do not normally express E-cadherin. But when they transform into epithelioid cells within a granuloma, they switch it on. Research using zebrafish infected with mycobacteria found robust E-cadherin expression in granuloma macrophages, both infected and uninfected ones. Within three days of infection, associated junction proteins were relocating to the points of cell-to-cell contact within the granuloma. Researchers identified not just adherens junctions but also classical desmosomes and tight junctions between granuloma macrophages, structures normally found only in true epithelial tissue.⁴ This is remarkable because tight junctions are the structures that make epithelial barriers waterproof, preventing molecules from leaking between cells. Their presence in granulomas suggests that epithelioid cells are creating a genuinely sealed compartment, not just a loose cluster.

The practical importance of this molecular adhesion became clear when researchers disrupted E-cadherin function specifically in macrophages. Without cadherin-mediated adhesion, the resulting granulomas were structurally disorganized.⁵ The epithelioid transformation, in other words, is not decorative. It is functionally essential for building a coherent, organized structure.

The Architecture of a Granuloma

To understand what epithelioid cells do, you need to picture the structure they create. A granuloma is a compact, roughly spherical cluster of immune cells that forms around something the body wants to contain. At the center sit the epithelioid cells, tightly packed together. These may merge with one another to form multinucleated giant cells, which are essentially epithelioid cells that have fused, creating single enormous cells with many nuclei. Surrounding this core is a cuff of lymphocytes (the T and B cells that coordinate the immune response), along with other supporting cells and fibroblasts.⁶

The organization is not random. In tuberculosis granulomas, researchers have observed that the tightness of this arrangement affects how the lesion behaves. Loosely compacted granulomas allow intimate contact between lymphocytes and macrophages, which appears to promote faster resolution. In contrast, the most slowly resolving lesions tend to have rigidly compartmentalized zones where lymphocytes and macrophages are separated and have limited contact with each other.⁶ The degree of epithelioid cell organization, then, helps determine whether a granuloma successfully contains a threat or becomes a chronic, unresolved lesion.

What Epithelioid Cells Produce

Epithelioid cells are not just bricks in a wall. They are metabolically active and secrete biologically important molecules. Two of the best-studied products are angiotensin-converting enzyme (ACE) and interleukin-1 (IL-1). In laboratory experiments using epithelioid cells isolated from rabbit lung granulomas, the cells actively produced both ACE and IL-1 in culture. IL-1 production increased substantially when the cells were stimulated, suggesting they can ramp up inflammatory signaling when needed.⁷

The ACE connection has real clinical relevance. In sarcoidosis, a disease characterized by granuloma formation throughout the body, blood levels of ACE are often elevated. Researchers traced this elevation to its source by using immunofluorescence to pinpoint ACE within sarcoidosis granulomas. They found intense ACE expression in the epithelioid cells and giant cells of sarcoidosis granulomas, but not in granulomas from other conditions.⁸ This is why doctors use serum ACE levels as a diagnostic marker when sarcoidosis is suspected: the epithelioid cells themselves are the factory pumping out the enzyme.

Containment That Cuts Both Ways

The conventional view of granulomas is that they protect the host by walling off dangerous pathogens. In tuberculosis, epithelioid cells form a barrier around Mycobacterium tuberculosis, preventing the bacteria from spreading to other tissues. Both too few and too many epithelioid macrophages have been reported to push granulomas toward a less protective form, suggesting that a precise, well-coordinated immune response is needed for effective containment.⁹

But the picture is more nuanced than “granulomas protect the host.” When researchers disrupted E-cadherin function in macrophages, preventing them from forming proper epithelioid cell junctions, the resulting disorganized granulomas actually allowed more immune cells to access the bacteria inside. The result was decreased bacterial burden and increased host survival.⁴ In other words, the very seal that epithelioid cells create can also shelter bacteria from the immune system. The granuloma becomes a kind of fortress that protects whatever is inside it, whether that is good for the host or not.

This finding has shifted how researchers think about granulomas in tuberculosis and related mycobacterial infections. Rather than viewing them purely as a host defense mechanism, the current understanding is that granulomas serve both sides of the host-pathogen struggle. The tight epithelioid barrier prevents bacterial spread but also prevents full immune clearance, creating a standoff that can persist for decades in latent tuberculosis.

Epithelioid Cells in Sarcoidosis and Foreign Body Reactions

Granulomas do not form only in response to infections. In sarcoidosis, the immune system builds granulomas without any identifiable pathogen. The histological hallmark of sarcoidosis is the non-caseating granuloma containing epithelioid cells, meaning the granuloma’s core does not undergo the cheese-like tissue death seen in tuberculosis.¹⁰ These granulomas can appear in virtually any organ, though the lungs and lymph nodes are most common. The epithelioid cells in sarcoidosis granulomas are the source of the elevated serum ACE levels that clinicians use to support diagnosis, as described earlier.

The body also deploys epithelioid cells against non-biological foreign materials. When something is implanted or lodged in tissue that cannot be digested or broken down, macrophages arrive and transform into epithelioid cells that attempt to encapsulate the object. Research into this foreign body response has found that the macrophages involved do not simply stay as conventional immune cells or turn into fibroblasts. Instead, they follow a distinct trajectory, expressing genes associated with tissue remodeling early on and then shifting to a mixed pattern of inflammatory and mesenchymal gene expression. Researchers have proposed these cells warrant their own category as “fibroblastoid” macrophages, underscoring that the epithelioid transformation sits along a broader spectrum of macrophage plasticity rather than representing a single fixed cell type.

The “Epithelioid” Label in Cancer

Confusingly, the word “epithelioid” also appears in oncology, where it describes a specific growth pattern in certain cancers. Epithelioid mesothelioma, the most common subtype of malignant pleural mesothelioma, gets its name because the tumor cells resemble epithelial cells in shape. These malignant cells are entirely unrelated to the epithelioid cells of granulomas. They are cancerous mesothelial cells, not transformed macrophages. The shared name reflects shared appearance, nothing more, and it can cause confusion when patients encounter the term.

Distinguishing epithelioid mesothelioma from lung carcinoma is a genuine diagnostic challenge because the cells can look similar under a microscope. Pathologists rely on panels of immunohistochemical markers to tell them apart. In one study comparing epithelioid mesotheliomas with squamous lung carcinomas, all mesotheliomas stained positive for calretinin, mesothelin, and keratin 7, while none stained positive for markers like CEA or TTF-1. The squamous carcinomas showed the inverse pattern. A practical approach using two positive mesothelioma markers (WT1 and calretinin or mesothelin) alongside two negative markers (p63 and MOC-31) could distinguish the two cancers in nearly all cases.¹¹

Similar marker panels have been validated for distinguishing epithelioid mesothelioma from lung adenocarcinoma. In a study of 90 epithelioid mesotheliomas and 51 lung adenocarcinomas, about 96 percent of mesotheliomas were positive for calretinin and 99 percent for WT1, compared with only about a third and 16 percent of adenocarcinomas, respectively. The combination of CEA, calretinin, and WT1 was suggested as the most effective panel for separating these two diagnoses.¹² A separate analysis focusing on poorly differentiated squamous cell carcinoma found that WT1 had the highest diagnostic accuracy as a mesothelioma marker, while CEA and p40 performed best as carcinoma markers.¹³

When Granulomas Obscure a Cancer Diagnosis

Beyond the naming confusion, there is a genuine diagnostic overlap between epithelioid granulomas and cancer. Granulomas sometimes form within or adjacent to tumors, and in rare instances the epithelioid cell response can be so florid that it obscures the underlying malignancy. Tumor cells can also mimic epithelioid histiocytes, creating difficulty in determining whether a lesion is reactive or neoplastic.¹⁴ When pathologists encounter granulomas in a biopsy specimen, the overt malignant features typically make the diagnosis straightforward. The trouble arises in that small minority of cases where the granulomatous reaction dominates the microscopic picture and the cancer hides underneath.

This is one reason pathologists are trained to look beyond the granuloma itself when they find one in tissue. A granuloma is always a sign that the immune system is responding to something, but what that something is ranges from a common infection to a systemic inflammatory disease to, occasionally, a malignancy provoking a granulomatous immune response in surrounding tissue.

Epithelioid Cells in Fish and What That Tells Us

The epithelioid cell response is not unique to mammals. Researchers studying chronic inflammation in bony fish (teleosts) found cells that share many hallmarks of mammalian epithelioid cells, including high metabolic activity, frequent digestive compartments, and cytoplasmic interdigitations between neighboring cells. Even more striking, these fish epithelioid cells formed granulomas with genuine epithelial features: they were joined by well-formed desmosomes with tonofilaments, and in Atlantic menhaden with a fungal disease, the mature granulomas stained positive for cytokeratin, a structural protein normally considered highly specific to true epithelial cells.¹⁵

The fact that fish, which diverged from mammals hundreds of millions of years ago, independently deploy an epithelial-like transformation in their macrophages during chronic inflammation suggests this strategy is ancient and deeply useful. Walling off a persistent threat behind a sealed barrier of transformed immune cells appears to be a solution that evolution has arrived at more than once, or perhaps preserved from a very early common ancestor. The consistent presence of these epithelial features in fish granulomas, including desmosome formation and cytokeratin expression, points to a conserved biological toolkit that macrophages can access when simple engulfment and digestion are not enough.

Fibrosis and What Happens When Granulomas Resolve

Granulomas are not meant to last forever, though some do. When the underlying trigger is cleared, the organized structure begins to disband. Epithelioid cells can revert to a less activated macrophage state, undergo programmed cell death, or be gradually replaced by fibroblasts that deposit collagen, leaving behind a small scar. In some situations, particularly when the granulomatous inflammation has been prolonged or severe, the resolution process tips toward fibrosis, the excessive deposition of connective tissue that stiffens and distorts the affected organ. In the lung, for instance, certain cells involved in tissue repair can either die off or revert to a resting state during fibrosis resolution.¹⁶

This is clinically relevant because diseases like sarcoidosis and tuberculosis can leave lasting damage not from the infection itself but from the immune response. The very epithelioid cells that contained the original threat can, through their sustained presence and secretory activity, contribute to tissue remodeling that outlives the granuloma. Pulmonary fibrosis in sarcoidosis patients, for example, represents the downstream consequence of granulomatous inflammation that never fully switched off. Understanding how epithelioid cells transition into, and eventually out of, their activated state remains one of the open questions in granuloma biology, and one with direct implications for preventing organ damage in chronic granulomatous diseases.