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Keratinocyte
Keratinocyte
Keratinocyte
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Micrograph of keratinocytes, basal cells and melanocytes in the epidermis
Keratinocytes (stained green) in the skin of a mouse

Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.[1] Basal cells in the basal layer (stratum basale) of the skin are sometimes referred to as basal keratinocytes.[2] Keratinocytes form a barrier against environmental damage by heat, UV radiation, water loss, pathogenic bacteria, fungi, parasites, and viruses. A number of structural proteins, enzymes, lipids, and antimicrobial peptides contribute to maintain the important barrier function of the skin. Keratinocytes differentiate from epidermal stem cells in the lower part of the epidermis and migrate towards the surface, finally becoming corneocytes and eventually being shed,[3][4][5][6] which happens every 40 to 56 days in humans.[7]

Function

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The primary function of keratinocytes is the formation of a barrier against environmental damage by heat, UV radiation, dehydration, pathogenic bacteria, fungi, parasites, and viruses.

Pathogens invading the upper layers of the epidermis can cause keratinocytes to produce proinflammatory mediators, particularly chemokines such as CXCL10 and CCL2 (MCP-1) which attract monocytes, natural killer cells, T-lymphocytes, and dendritic cells to the site of pathogen invasion.[8]

Structure

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A number of structural proteins (filaggrin, keratin), enzymes (e.g. proteases), lipids, and antimicrobial peptides (defensins) contribute to maintain the important barrier function of the skin. Keratinization is part of the physical barrier formation (cornification), in which the keratinocytes produce more and more keratin and undergo terminal differentiation. The fully cornified keratinocytes that form the outermost layer are constantly shed off and replaced by new cells.[3]

Cell differentiation

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Epidermal stem cells reside in the lower part of the epidermis (stratum basale) and are attached to the basement membrane through hemidesmosomes. Epidermal stem cells divide in a random manner yielding either more stem cells or transit amplifying cells.[4] Some of the transit amplifying cells continue to proliferate then commit to differentiate and migrate towards the surface of the epidermis. Those stem cells and their differentiated progeny are organized into columns named epidermal proliferation units.[5]

During this differentiation process, keratinocytes permanently withdraw from the cell cycle, initiate expression of epidermal differentiation markers, and move suprabasally as they become part of the stratum spinosum, stratum granulosum, and eventually corneocytes in the stratum corneum.

Corneocytes are keratinocytes that have completed their differentiation program and have lost their nucleus and cytoplasmic organelles.[6] Corneocytes will eventually be shed off through desquamation as new ones come in.

At each stage of differentiation, keratinocytes express specific keratins, such as keratin 1, keratin 5, keratin 10, and keratin 14, but also other markers such as involucrin, loricrin, transglutaminase, filaggrin, and caspase 14.

In humans, it is estimated that keratinocytes turn over from stem cells to desquamation every 40–56 days,[7] whereas in mice the estimated turnover time is 8–10 days.[9]

Factors promoting keratinocyte differentiation are:

  • A calcium gradient, with the lowest concentration in the stratum basale and increasing concentrations until the outer stratum granulosum, where it reaches its maximum. Calcium concentration in the stratum corneum is very high in part because those relatively dry cells are not able to dissolve the ions.[10] Those elevations of extracellular calcium concentrations induces an increase in intracellular free calcium concentrations in keratinocytes.[11] Part of that intracellular calcium increase comes from calcium released from intracellular stores[12] and another part comes from transmembrane calcium influx,[13] through both calcium-sensitive chloride channels[14] and voltage-independent cation channels permeable to calcium.[15] Moreover, it has been suggested that an extracellular calcium-sensing receptor (CaSR) also contributes to the rise in intracellular calcium concentration.[16]
  • Vitamin D3 (cholecalciferol) regulates keratinocyte proliferation and differentiation mostly by modulating calcium concentrations and regulating the expression of genes involved in keratinocyte differentiation.[17][18] Keratinocytes are the only cells in the body with the entire vitamin D metabolic pathway from vitamin D production to catabolism and vitamin D receptor expression.[19]
  • Cathepsin E.[20]
  • TALE homeodomain transcription factors.[21]
  • Hydrocortisone.[22]

Since keratinocyte differentiation inhibits keratinocyte proliferation, factors that promote keratinocyte proliferation should be considered as preventing differentiation. These factors include:

Interaction with other cells

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Within the epidermis keratinocytes are associated with other cell types such as melanocytes and Langerhans cells. Keratinocytes form tight junctions with the nerves of the skin and hold the Langerhans cells and intra-dermal lymphocytes in position within the epidermis. Keratinocytes also modulate the immune system: apart from the above-mentioned antimicrobial peptides and chemokines they are also potent producers of anti-inflammatory mediators such as IL-10 and TGF-β. When activated, they can stimulate cutaneous inflammation and Langerhans cell activation via TNFα and IL-1β secretion.[citation needed]

Keratinocytes contribute to protecting the body from ultraviolet radiation (UVR) by taking up melanosomes, vesicles containing the endogenous photoprotectant melanin, from epidermal melanocytes. Each melanocyte in the epidermis has several dendrites that stretch out to connect it with many keratinocytes. The melanin is then stored within keratinocytes and melanocytes in the perinuclear area as supranuclear "caps", where it protects the DNA from UVR-induced damage.[28]

Role in wound healing

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Wounds to the skin will be repaired in part by the migration of keratinocytes to fill in the gap created by the wound. The first set of keratinocytes to participate in that repair come from the bulge region of the hair follicle and will only survive transiently. Within the healed epidermis they will be replaced by keratinocytes originating from the epidermis.[29][30]

At the opposite, epidermal keratinocytes, can contribute to de novo hair follicle formation during the healing of large wounds.[31]

Functional keratinocytes are needed for tympanic perforation healing.[32]

Sunburn cells

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A sunburn cell is a keratinocyte with a pyknotic nucleus and eosinophilic cytoplasm that appears after exposure to UVC or UVB radiation or UVA in the presence of psoralens. It shows premature and abnormal keratinization, and has been described as an example of apoptosis.[33][34]

Aging

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With age, tissue homeostasis declines partly because stem/progenitor cells fail to self-renew or differentiate. DNA damage caused by exposure of stem/progenitor cells to reactive oxygen species (ROS) may play a key role in epidermal stem cell aging. Mitochondrial superoxide dismutase (SOD2) ordinarily protects against ROS. Loss of SOD2 in mouse epidermal cells was observed to cause cellular senescence that irreversibly arrested proliferation in a fraction of keratinocytes.[35] In older mice, SOD2 deficiency delayed wound closure and reduced epidermal thickness.[35]

Civatte body

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Civatte body

A Civatte body (named after the French dermatologist Achille Civatte, 1877–1956)[36] is a damaged basal keratinocyte that has undergone apoptosis, and consist largely of keratin intermediate filaments, and are almost invariably covered with immunoglobulins, mainly IgM.[37] Civatte bodies are characteristically found in skin lesions of various dermatoses, particularly lichen planus and discoid lupus erythematosus.[37] They may also be found in graft-versus-host disease, adverse drug reactions, inflammatory keratosis (such as lichenoid actinic keratosis and lichen planus-like keratosis), erythema multiforme, bullous pemphigoid, eczema, lichen planopilaris, febrile neutrophilic dermatosis, toxic epidermal necrolysis, herpes simplex and varicella zoster lesions, dermatitis herpetiformis, porphyria cutanea tarda, sarcoidosis, subcorneal pustular dermatosis, transient acantholytic dermatosis and epidermolytic hyperkeratosis.[37]

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Keratinocyte

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Keratinocytes are the predominant cells in the , the outermost layer of the skin, originating from stem cells in the basal layer () and undergoing a process of differentiation to form the protective barrier against environmental insults. These cells, which constitute about 90% of the epidermal cell population, synthesize proteins called keratins and that are essential for the skin's water-impermeable barrier function, preventing dehydration and entry. As they differentiate, keratinocytes transition from cuboidal or columnar shapes in the basal layer to flattened, anucleate squamous cells in the , where they eventually desquamate to renew the skin surface. Beyond their structural role, keratinocytes play critical functions in innate immunity and by acting as sentinels that detect pathogens through Toll-like receptors (TLRs), such as TLR3 and TLR4, triggering the release of cytokines (e.g., IL-1, IL-6, TNF-α), , and like β-defensins and LL-37. In response to injury, they promote re-epithelialization through proliferation, migration, and differentiation, while interacting with immune cells like neutrophils and macrophages via extracellular vesicles and growth factors such as GM-CSF to resolve and restore tissue integrity. Dysregulation of keratinocyte functions is implicated in conditions like chronic wounds, where persistent impairs barrier repair, and inflammatory skin diseases, highlighting their multifaceted role in skin homeostasis.

Structure

Morphology

Keratinocytes constitute approximately 90% of the cells in the human epidermis, the outermost layer of the skin, and are the primary cellular component responsible for its stratified structure. These cells originate as proliferative precursors in the , the deepest epidermal layer, and migrate upward through successive strata—spinosum, granulosum, and corneum—in a process driven by terminal differentiation and . This migration results in profound morphological transformations that adapt the cells for , with the entire epidermal turnover cycle spanning 40–56 days in humans. In the stratum basale, keratinocytes appear as a single layer of cuboidal to columnar cells, typically 10–15 μm in height, with large, ovoid nuclei occupying much of the . These basal cells are anchored to the underlying by hemidesmosomes, facilitating their role as progenitors, while their contains organelles such as mitochondria, ribosomes, and early bundles of intermediate filaments. As cells leave this layer, they enlarge slightly and transition to the stratum spinosum, where they adopt an irregular polyhedral shape, reaching 20–30 μm in diameter. Here, keratinocytes develop prominent desmosomal junctions that interconnect adjacent cells, visible under light microscopy as spiny projections due to artifactual shrinkage during tissue preparation; electron microscopy further reveals dense tonofilaments—keratin intermediate filaments—inserting into the electron-dense plaques of these desmosomes, enhancing intercellular cohesion. Progressing to the , keratinocytes flatten into diamond- or ovoid-shaped cells, approximately 10–20 μm thick, with 3–5 layers stacking to form a transitional zone. These granular cells feature pyknotic, degenerating nuclei and are distinguished by basophilic granules (1–5 μm in diameter) that aggregate with tonofilaments to initiate cross-linking, alongside lamellar granules that secrete for intercellular sealing. Electron micrographs show tonofilaments becoming more aggregated and interspersed with these granules, marking the onset of nuclear pyknosis and cytoplasmic compaction. At the surface, in the , keratinocytes terminally differentiate into anucleate corneocytes—highly flattened, scalelike cells 0.5–1 μm thick and 20–30 μm wide—arranged in 15–30 compact layers that vary by body region (thicker on palms and soles). These enucleated cells are filled with a filament network embedded in a filaggrin-rich matrix, providing rigidity and waterproofing; desmosomal junctions persist initially but degrade during , allowing superficial shedding. Under electron , corneocytes exhibit a homogenous, electron-dense keratin interior devoid of organelles, with residual desmosomal remnants facilitating controlled exfoliation.

Composition

Keratinocytes are characterized by their cytoskeletal framework composed primarily of intermediate filaments made from proteins, which provide mechanical strength and . These keratins are divided into type I (acidic) and type II (basic) families, forming obligatory heterodimers essential for filament assembly. In basal keratinocytes, the predominant pair is K5 (type II) and K14 (type I), while suprabasal keratinocytes express K1 (type II) and K10 (type I). Keratin dimerization occurs through the association of their central alpha-helical rod domains into a coiled-coil structure, where two alpha-helices wrap around each other in a parallel orientation stabilized by hydrophobic interactions along heptad repeats. Associated with these keratin filaments are proteins that facilitate their organization and integration into higher-order structures. binds to and bundles the keratin filaments, promoting their compaction during the later stages of keratinocyte development. Involucrin serves as a key in the cornified envelope, a specialized layer beneath the plasma of terminally differentiated keratinocytes, where it undergoes cross-linking to form a rigid barrier. Keratinocytes also synthesize and package lipids within lamellar bodies, which are organelles abundant in the granular layer. These bodies contain ceramides, , and free fatty acids, which are extruded extracellularly to contribute to the intercellular matrix. Enzymes such as transglutaminases, particularly transglutaminase-1, catalyze the cross-linking of proteins like involucrin and other envelope precursors, ensuring the envelope's insolubility and durability. Additionally, keratinocytes store within cytoplasmic granules, including beta-defensins and cathelicidin, which are packaged alongside in lamellar bodies for release upon cellular stress.

Function

Barrier Formation

Keratinocytes establish the skin's primary barrier through cornification, a terminal differentiation process that transforms viable cells in the into anucleated corneocytes in the . During cornification, keratinocytes lose their nuclei and organelles via , while their fills with cross-linked filaments embedded in a matrix, providing structural rigidity. Concurrently, lamellar bodies within keratinocytes extrude non-polar —such as ceramides, , and free fatty acids—into the intercellular spaces, forming a hydrophobic matrix that seals the barrier. This results in the "bricks and mortar" architecture, where flattened corneocytes serve as the impermeable bricks and the lipid bilayers act as the mortar, collectively preventing penetration by external agents. The stratum corneum's barrier function critically minimizes (TEWL), preserving internal hydration by limiting passive diffusion of water and electrolytes across the matrix, which exhibits low permeability due to its orthogonal arrangement of lamellae. Mechanical integrity is further ensured by desmosomal junctions, which anchor intermediate filaments across corneocytes, distributing tensile forces and conferring resistance to shear and abrasion; keratins K1 and K10, expressed suprabasally, enhance this rigidity by forming robust filament bundles. These properties collectively enable the to withstand environmental stresses without compromising underlying tissues. Acidification of the stratum corneum's outer layers, achieving a of approximately 4.5–5.5, is regulated by keratinocytes through the proteolytic degradation of histidine-rich into acidic free and the activity of lipid-processing enzymes with optima in this range. This low environment exerts effects by inhibiting the growth and colonization of pathogenic bacteria, such as , while favoring commensal flora adapted to acidity, thereby supporting chemical barrier without relying on active immune responses. Barrier maintenance involves a continuous renewal cycle, where proliferation of basal keratinocytes generates new cells that migrate upward, differentiating into corneocytes over approximately 40–56 days to replenish the . Superficial corneocytes in the stratum disjunctum undergo through proteolytic cleavage of corneodesmosomes by proteases, regulated by the acidic pH, ensuring orderly shedding without disrupting barrier integrity; this balances turnover to sustain a functional 10–20 cell-thick layer.

Protection and Immune Modulation

Keratinocytes play a crucial role in the skin's protective mechanisms by actively responding to environmental stressors such as and through the production of proinflammatory mediators. Upon sensing damage or microbial invasion via receptors like Toll-like receptors, keratinocytes rapidly secrete cytokines including interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), which amplify local and recruit immune cells to the site of threat. Similarly, they release such as C-X-C motif chemokine ligand 10 () and C-C motif chemokine ligand 2 (), which guide the migration of neutrophils, monocytes, and T cells to enhance the innate and early adaptive responses. These soluble factors not only initiate a coordinated defense but also prevent dissemination by promoting and cellular activation. In addition to cytokine signaling, keratinocytes contribute to innate immunity by synthesizing and releasing antimicrobial peptides (AMPs) that directly combat microbial threats. Key AMPs produced by keratinocytes include cathelicidins, such as the human peptide LL-37, and β-defensins (e.g., human β-defensin-2 and -3), which are stored in lamellar bodies and secreted into the extracellular space upon stimulation by injury or infection. These peptides exhibit broad-spectrum activity against bacteria, fungi, and viruses by disrupting microbial membranes and modulating host immune responses, thereby forming a chemical barrier that complements physical defenses. Expression of these AMPs is upregulated in response to proinflammatory signals, ensuring a rapid escalation of antimicrobial activity at sites of compromise. Keratinocytes also provide specialized protection against ultraviolet (UV) radiation through melanin acquisition and intrinsic DNA maintenance pathways. Melanosomes containing melanin are transferred from neighboring melanocytes to keratinocytes, where the pigment aggregates supranuclearly to absorb UV photons and scavenge reactive oxygen species, thereby shielding nuclear DNA from photolesions. In cases of irreparable UV-induced DNA damage, keratinocytes activate DNA repair enzymes via nucleotide excision repair mechanisms regulated by the tumor suppressor protein p53, which can trigger apoptosis in severely affected cells to eliminate potential precancerous mutations and preserve tissue integrity. This p53-dependent apoptosis acts as a sacrificial mechanism, preventing the propagation of genomic instability. Beyond innate defenses, keratinocytes modulate adaptive immunity by functioning as non-professional -presenting cells, processing and displaying s on () class I and II molecules to T lymphocytes. Under inflammatory conditions, they upregulate MHC expression and costimulatory molecules such as (B7-1), which provide the second signal necessary for T cell priming and differentiation, thereby bridging innate detection to long-term adaptive responses. This capability allows keratinocytes to influence T cell polarization and effector functions, including brief signaling to resident dendritic cells like Langerhans cells for enhanced surveillance.

Differentiation

Proliferation and Stem Cells

Keratinocytes originate from stem cells located in the basal layer of the , known as the . These stem cells maintain the epidermal population through controlled division, ensuring continuous renewal of the skin barrier. In interfollicular epidermis, basal stem cells reside among progenitor cells, while reserve stem cells are found in specialized niches such as the bulge region of hair follicles. Bulge cells serve as a quiescent reservoir, capable of mobilizing to replenish epidermal keratinocytes during or injury, contributing to long-term tissue maintenance. A key mechanism for maintenance is , where a basal divides to produce one daughter cell that retains properties and remains anchored to the , and another that becomes a transit-amplifying (TA) cell committed to differentiation. This process balances self-renewal and production of progenitors, preventing depletion of the pool while generating cells that will migrate upward. Asymmetric divisions are oriented perpendicular to the , ensuring proper fate specification through unequal inheritance of cellular components like proteins and organelles. Cell cycle progression in basal keratinocytes is tightly regulated by growth factors, including epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α), which bind to the EGF receptor to stimulate proliferation via pathways such as MAPK/ERK signaling. These factors promote entry into the cell cycle from G0/G1 phases, enhancing DNA synthesis and mitosis in stem and TA cells. Proliferation is commonly assessed using markers like Ki-67, a nuclear protein expressed during active cell cycling (G1, S, G2, and M phases) but absent in quiescent or differentiated cells, allowing quantification of dividing basal populations. In humans, the overall epidermal turnover time is approximately 40-56 days, reflecting a low daily division rate among basal keratinocytes to match the slow renewal of the full stratified . This equates to roughly 1-2% of basal cells entering the daily under homeostatic conditions, with stem cells comprising only 1-10% of the basal layer and dividing infrequently to sustain long-term . In contrast, mice exhibit faster epidermal dynamics, with a full turnover cycle of 8-10 days, driven by higher basal proliferation rates that support rapid regeneration. Following division, TA cells undergo a limited number of symmetric divisions before exiting the basal layer and initiating differentiation. Clonal assays provide a functional means to identify and characterize keratinocyte stem cells . Holoclones, formed by stem cells, are large, smooth-edged colonies with high proliferative potential and the ability to generate both stem and differentiated progeny over multiple passages, reflecting self-renewal capacity. In contrast, paraclones arise from committed TA cells and consist of small, abortive colonies with limited divisions, leading to terminal differentiation. Meroclones represent an intermediate state, derived from partially committed progenitors. This , established through serial subcloning, distinguishes stem cell potency and has been instrumental in isolating epidermal stem populations since its development in the late and refinements in the .

Maturation Process

Keratinocytes undergo a tightly regulated maturation process as they differentiate from proliferative basal cells to terminally differentiated corneocytes, involving sequential biochemical and structural transformations that ensure epidermal integrity. This differentiation begins in the basal layer, where keratinocytes express keratins 5 and 14 (K5/K14), which provide and maintain proliferative capacity. As cells commit to differentiation and migrate suprabasally, a key event known as the keratin switch occurs, downregulating K5/K14 expression while upregulating keratins 1 and 10 (K1/K10), along with desmoglein 1 for enhanced . This switch, driven by transcriptional changes, marks the transition to the spinous layer, where early differentiation markers like involucrin appear in the upper spinous keratinocytes, initiating cross-linking precursors for the cornified envelope. In the granular layer, maturation advances with the expression of late markers such as and loricrin, which aggregate into granules to facilitate barrier formation, and in the granular keratinocytes, which catalyzes protein cross-linking. Lamellar bodies, synthesized in this layer, secrete and enzymes that contribute to the intercellular barrier, while structural changes include the formation of tight junctions via claudin-1. The process culminates in the cornified layer through an apoptosis-like cornification, where keratinocytes undergo nuclear degradation and formation without complete ; cross-links loricrin, , and involucrin to create a rigid, insoluble cornified , releasing the cell as a corneocyte. Transcription factors play critical roles in orchestrating these stages: Notch signaling activates upon suprabasal commitment, promoting growth arrest and differentiation by upregulating genes like those for K1/K10 and involucrin, while PPARγ enhances and terminal differentiation, with cross-talk between Notch and PPARγ stabilizing PPARγ protein to drive maturation. The entire maturation timeline, from basal proliferation to corneocyte shedding, spans approximately 40-56 days in under normal conditions.

Cellular Interactions

With Epidermal Cells

Keratinocytes engage in a symbiotic relationship with melanocytes within the epidermal melanin unit, where keratinocytes secrete stem cell factor (SCF) to bind c-KIT receptors on melanocytes, thereby supporting their survival, proliferation, and melanin production. In exchange, melanocytes transfer melanosomes—pigment-laden organelles—to keratinocytes through mechanisms such as cytocrine secretion and phagocytosis, enabling the formation of supranuclear melanin caps that shield keratinocyte DNA from ultraviolet (UV) radiation damage. This bidirectional exchange ensures skin pigmentation and photoprotection, with UV exposure enhancing melanosome uptake in keratinocytes to bolster the defensive barrier. Keratinocytes and melanocytes maintain direct intercellular communication via gap junctions, which facilitate the exchange of ions, metabolites, and signaling molecules to regulate melanogenesis; disruption of these junctions, as shown in coculture experiments using blockers like , reduces expression of key melanogenic enzymes such as in melanocytes. Complementing this, keratinocytes release paracrine factors including endothelin-1 (EDN1), which activates receptor B on melanocytes to promote their proliferation, dendrite extension, and pigmentation, particularly in response to UV-induced signaling in keratinocytes. These interactions underscore the keratinocytes' role in orchestrating melanocyte function for adaptive skin responses. Interactions between keratinocytes and Merkel cells, specialized mechanosensory cells derived from or closely associated with keratinocytes, primarily occur in epidermal touch domes, where keratinocytes provide structural support and potential signaling cues for tactile sensation; these dome keratinocytes express unique markers like tenascin-C, enabling intimate association with Merkel cells to aid in light touch transduction via Piezo2 channels, though direct keratinocyte-Merkel signaling remains limited compared to neuronal . In hair follicles, follicular keratinocytes interact with matrix keratinocytes—transient amplifying cells in the bulb region—to drive formation; signaling from outer root sheath and bulge keratinocytes regulates matrix cell proliferation and differentiation into hair shaft structures like the cortex and medulla, ensuring cyclic growth through pathways involving Wnt and BMP inhibitors. Similar epithelial interactions occur in nail matrix keratinocytes, where proliferation and alignment produce nail plates, though these are less studied than follicular dynamics.

With Immune Cells

Keratinocytes play a pivotal role in skin immune surveillance by recruiting , a subset of dendritic cells residing in the , through the secretion of specific . In particular, differentiated keratinocytes produce macrophage inflammatory protein 3α (MIP-3α/), a potent chemoattractant for expressing the CCR6 receptor, thereby facilitating their migration and positioning within the epidermal layer for antigen sampling. This recruitment process is tightly regulated by tumor necrosis factor-α (TNF-α), which keratinocytes themselves synthesize and release in response to environmental stimuli, enhancing expression to orchestrate localized immune patrolling. Additionally, during epidermal development, keratinocytes secrete and to mediate the immigration of precursors from the into the . Beyond recruitment, keratinocytes modulate the maturation and function of dendritic cells, including Langerhans cells, via cytokine production. Keratinocytes generate TNF-α, a pro-inflammatory cytokine that promotes dendritic cell maturation by upregulating co-stimulatory molecules and cytokine secretion, thereby enhancing antigen presentation capabilities. In contrast, keratinocytes also produce interleukin-10 (IL-10), an anti-inflammatory cytokine that inhibits dendritic cell maturation, suppresses pro-inflammatory cytokine release, and fosters a tolerogenic environment to prevent excessive immune activation. This dual cytokine output allows keratinocytes to fine-tune dendritic cell responses, balancing surveillance against overzealous inflammation. Keratinocytes interact directly with T cells, particularly under inflammatory conditions, by upregulating class II (MHC II) molecules to present antigens. In response to interferon-γ (IFN-γ) during , keratinocytes express MHC II on their surface, enabling them to process and display self-antigens or microbial peptides to + T cells, thereby initiating or amplifying adaptive immune responses. This capability positions keratinocytes as non-professional antigen-presenting cells that can activate naive or memory T cells in the skin microenvironment, contributing to localized T cell proliferation and effector function. Cross-talk between keratinocytes and macrophages involves reciprocal exchange to regulate inflammation. Keratinocytes secrete like (MCP-1), which recruits monocytes and macrophages to sites of perturbation, while also releasing such as IL-1 and TNF-α that activate macrophage and pro-inflammatory signaling. In return, macrophages provide feedback through anti-inflammatory mediators, enabling keratinocytes to limit excessive storms and restore ; for instance, IL-10 from both cell types dampens TNF-α-driven responses. A key mechanism by which keratinocytes promote involves the expression of programmed death-ligand 1 (). Keratinocytes express on their surface, which interacts with PD-1 on T cells to inhibit their and proliferation, thereby suppressing autoreactive responses and maintaining in the skin. This -mediated checkpoint underscores keratinocytes' role in preventing chronic inflammation through direct suppression of T cell effector functions.

Role in Wound Healing

Migration and Re-epithelialization

Upon , keratinocytes at the wound margin are activated by growth factors such as transforming growth factor-β (TGF-β) and (EGF), which trigger signaling pathways promoting motility and re-epithelialization. This activation involves downregulation of E-cadherin, facilitating an epithelial-to-mesenchymal transition (EMT)-like process that dissociates cell-cell adhesions and enhances individual and collective cell movement. Keratinocytes then engage in sheet migration, advancing as a cohesive from the edges to cover the denuded area. In humans, this process proceeds at a rate of approximately 0.5 mm per day, enabling rapid provisional closure of superficial . During migration, such as α6β4 play a critical role in mediating to the provisional , which primarily consists of and allows keratinocytes to traverse the bed while maintaining directional persistence. In addition to epidermal keratinocytes, stem cells from the bulge region serve as an auxiliary source, contributing migratory progeny that augment re-epithelialization, particularly in areas distant from the primary margin. This multi-compartmental recruitment ensures comprehensive coverage, with bulge-derived cells transiently integrating into the neo-epidermis before homeostatic restoration. Following successful migration and initial resurfacing, keratinocytes undergo hyperproliferation to restore multilayered epidermal architecture.

Hyperproliferation

Hyperproliferation of keratinocytes is a critical phase in that follows initial migration, involving accelerated in the basal layer to replenish lost epidermal tissue and restore barrier function. This process is primarily driven by from dermal fibroblasts, which secrete keratinocyte growth factor (KGF), also known as 7 (FGF7), to upregulate basal keratinocyte proliferation. In response, keratinocytes temporarily express hyperproliferative keratins such as K6, K16, and K17, which enhance cellular resilience and facilitate rapid tissue regeneration during this transient state. The hyperproliferative response contributes to the restoration of epidermal stratification by promoting swift upward transit of keratinocytes through the epidermal layers, often resulting in a thinner initial with altered differentiation patterns. This rapid progression is marked by abnormal expression of differentiation markers, such as premature or dysregulated involucrin and loricrin, reflecting an incomplete recapitulation of normal epidermal architecture to prioritize speed over perfection in barrier reformation. Hyperproliferation typically resolves within approximately two weeks as the reorganizes into a fully stratified layer, with proliferation rates returning to to prevent excessive tissue buildup. However, imbalances in this regulation, such as persistent signaling or dysregulated deposition, can lead to pathological scarring, including hypertrophic scars characterized by overproduction. At the molecular level, activation of the Wnt/β-catenin signaling pathway plays a pivotal role in sustaining keratinocyte proliferation during hyperproliferation, by stabilizing β-catenin to translocate to the nucleus and induce genes like that drive progression.

Pathological Aspects

Sunburn Cells

Sunburn cells represent a distinct population of apoptotic keratinocytes that emerge in the following acute exposure to (UV) radiation, particularly UVB wavelengths. These cells arise as a direct consequence of irreparable DNA damage inflicted by UV light, serving as a hallmark of the skin's acute response to solar . They typically manifest in the suprabasal layers of the , including the spinous and granular strata, and are most prominent 24 to 48 hours after UV irradiation. Morphologically, sunburn cells are identifiable by their shrunken cell bodies, pyknotic (condensed and darkly stained) nuclei, and (pink-staining) cytoplasm when observed via hematoxylin and eosin in histological sections. These features reflect the advanced stages of , including nuclear fragmentation and cytoplasmic condensation, distinguishing them from viable keratinocytes. The cells often exhibit perinuclear halos due to cytoplasmic shrinkage, further emphasizing their degenerative state. The formation of sunburn cells is initiated by UV-induced DNA lesions, such as cyclobutane and 6-4 photoproducts, which activate the tumor suppressor protein p53. This then upregulates pro-apoptotic genes, including Bax and Puma, triggering the intrinsic mitochondrial pathway of to eliminate severely damaged cells. This p53-dependent process ensures that keratinocytes harboring potentially mutagenic alterations do not proliferate, thereby mitigating the risk of . The incidence of sunburn cells is highly dose-dependent, with their numbers correlating directly to the intensity and duration of UV exposure; higher doses lead to greater rates. In experimental models, peak formation occurs following high UVB doses, such as those exceeding the minimal erythema dose by several fold. This variability underscores the skin's threshold-based response to UV stress. Biologically, sunburn cells embody a protective sacrificial mechanism, where the programmed death of damaged keratinocytes prevents the propagation of genetic errors that could lead to . The resulting cellular debris is efficiently cleared through by adjacent viable keratinocytes, minimizing and maintaining epidermal integrity without eliciting a strong .

Civatte Bodies

Civatte bodies, also known as or bodies, are round to oval, homogeneous, structures measuring 10-30 μm in diameter, typically located in the papillary and derived from apoptotic basal keratinocytes. These bodies form through apoptotic death of keratinocytes in interface dermatitides, such as and , where immune-mediated damage targets the basal layer, leading to cell fragmentation and extrusion into the ; they are often coated with IgM and complement components, reflecting opsonization during the apoptotic process. Detection occurs primarily through routine hematoxylin and eosin (H&E) staining, where they appear as pink, globular residues, with periodic acid-Schiff (PAS) stain highlighting their diastase-resistant positivity; electron microscopy reveals characteristic apoptotic features, including fragmented nuclei and condensed within these remnants. Clinically, Civatte bodies serve as a histological marker of autoimmune or cytotoxic attack on the epidermal basal layer in inflammatory conditions, aiding of interface dermatitides, though they lack specificity to any single disease and can appear in various lichenoid reactions.

Effects of Aging

Aging profoundly impacts keratinocyte , leading to a decline in skin's and regenerative capacity. As individuals age, keratinocytes exhibit reduced proliferative potential, primarily due to slower division of epidermal stem cells and progressive shortening, which limits their replicative lifespan. This is exacerbated by the accumulation of (ROS), linked to downregulation of 2 (SOD2), an enzyme crucial for mitochondrial protection in keratinocytes. Consequently, aged keratinocytes enter a state of replicative , marked by persistent DNA damage response activation and β-galactosidase expression, impairing overall epidermal renewal. Differentiation processes in keratinocytes are also disrupted with age, resulting in a thinner epidermis and delayed cornification. Elderly skin shows a relatively stable or slightly increased stratum corneum thickness and altered expression of differentiation markers like involucrin and loricrin, leading to increased transepidermal water loss and heightened permeability to external irritants. These changes stem from impaired calcium signaling and altered keratin filament organization, which compromise the structural integrity of the epidermal barrier. Studies on human skin biopsies from individuals over 70 years reveal a 20-30% reduction in keratinocyte layers compared to younger cohorts, underscoring the progressive atrophy. The effects of aging extend to , where keratinocytes play a central role but demonstrate diminished efficiency. In aged individuals, re-epithelialization is weakened by prolonged phases and reduced keratinocyte migration, with clinical studies reporting slower closure rates in those over 65 compared to younger adults. This delay arises from decreased expression of growth factors like (EGF) and impaired signaling pathways, such as MAPK, which hinder collective keratinocyte movement to cover . Animal models corroborate these findings, showing that senescent keratinocytes secrete pro-inflammatory cytokines, perpetuating and . Furthermore, aging keratinocytes display heightened sensitivity to ultraviolet (UV) radiation, increasing the formation of sunburn cells—apoptotic keratinocytes resulting from DNA damage. This vulnerability is attributed to declined nucleotide excision repair (NER) mechanisms, with aged cells showing decreased repair efficiency for UV-induced cyclobutane pyrimidine dimers. Recent research as of 2025 highlights that the senescence-associated secretory phenotype (SASP) in keratinocytes amplifies UV-induced apoptosis and contributes to long-term photoaging responses in vivo, including through pathways like cGAS-STING signaling.

Involvement in Diseases

Keratinocytes play a central in the pathogenesis of (cSCC), where mutations in the TP53 gene represent an early and critical event leading to inactivation of the tumor suppressor protein and subsequent neoplastic transformation of epidermal keratinocytes. These TP53 mutations are detected in up to 90% of cSCC cases and nearly 100% of precursor actinic keratoses, highlighting their ubiquity in keratinocyte-derived tumorigenesis driven by ultraviolet . In contrast, (BCC), the most common keratinocyte malignancy, arises from basaloid keratinocytes but involves indirect stromal influences, where tumor-stroma interactions promote aberrant proliferation and invasion through signaling pathways like YAP-mediated regulation of components. In inflammatory skin disorders, keratinocytes contribute to through hyperproliferation marked by upregulation of keratins K6 and K16, which serve as diagnostic indicators of epidermal turnover in lesional skin. This hyperproliferative state is mediated by the , where activation of in keratinocytes amplifies inflammatory cytokine responses and sustains plaque formation. In , loss-of-function mutations in the (FLG) gene impair keratinocyte terminal differentiation and compromise the epidermal barrier, increasing and susceptibility to allergens in up to 20-30% of patients. Autoimmune conditions further implicate keratinocytes as targets of immune dysregulation. In , basal keratinocytes undergo , forming Civatte bodies that represent fragmented keratinocyte debris at the dermoepidermal junction and contribute to the characteristic interface dermatitis. In , altered keratinocyte signaling, including reduced production of melanocyte survival factors like WNT proteins, promotes melanocyte detachment and loss, exacerbating in lesional skin. Therapeutic strategies targeting keratinocyte dysfunction have advanced significantly. Stem cell-derived keratinocytes, including those from induced pluripotent stem cells, accelerate re-epithelialization in severe burns by enhancing and formation when transplanted autologously or allogeneically. Recent developments (2020-2025) include topical combinations of and , which inhibit to normalize cholesterol metabolism in hyperproliferative keratinocytes, reducing proliferation in conditions like porokeratosis as shown in Journal of Investigative Dermatology studies. For BCC, hedgehog pathway inhibitors such as vismodegib and sonidegib directly block aberrant signaling in keratinocytes, inducing tumor regression in advanced cases with response rates exceeding 40%.

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