Inflammasome Activation of IL-1 Family Mediators in Response to Cutaneous Photodamage

• Published in: Photochemistry and photobiology Vol. 88; no. 5; pp. 1111 - 1125
• Main Authors: Nasti, Tahseen H., Timares, Laura
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-2012
• Subjects: Apoptosis - immunology; Apoptosis - radiation effects; Cells; Cytokines; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA Repair - immunology; DNA Repair - radiation effects; Epidermis - cytology; Epidermis - immunology; Epidermis - radiation effects; Humans; Immunity, Innate - radiation effects; Inflammasomes - immunology; Inflammasomes - radiation effects; Inflammation - immunology; Interleukin-18 - immunology; Interleukin-18 - secretion; Interleukin-1alpha - immunology; Interleukin-1alpha - secretion; Interleukin-1beta - immunology; Interleukin-1beta - secretion; Interleukin-33; Interleukins - immunology; Interleukins - secretion; Keratinocytes - cytology; Keratinocytes - radiation effects; Mutation; Photobiology; Signal Transduction - immunology; Signal Transduction - radiation effects; Skin; Ultraviolet radiation; Ultraviolet Rays - adverse effects
• ISSN: 0031-8655; 1751-1097
• DOI: 10.1111/j.1751-1097.2012.01182.x

Although keratinocytes are relatively resistant to ultraviolet radiation (UVR) induced damage, repeated UVR exposure result in accumulated DNA mutations that can lead to epidermal malignancies. Keratinocytes play a central role in elaborating innate responses that lead to inflammation and influence the generation of adaptive immune responses in skin. Apart from the minor cellular constituents of the epidermis, specifically Langerhans cells and melanocytes, keratinocytes are the major source of cytokines. UVR exposure stimulates keratinocytes to secrete abundant pro‐inflammatory IL‐1‐family proteins, IL‐1α, IL‐1β, IL‐18, and IL‐33. Normal skin contains only low levels of inactive precursor forms of IL‐1β and IL‐18, which require caspase 1‐mediated proteolysis for their maturation and secretion. However, caspase‐1 activation is not constitutive, but dependents on the UV‐induced formation of an active inflammasome complex. IL‐1 family cytokines can induce a secondary cascade of mediators and cytokines from keratinocytes and other cells resulting in wide range of innate processes including infiltration of inflammatory leukocytes, induction of immunosuppression, DNA repair or apoptosis. Thus, the ability of keratinocytes to produce a wide repertoire of proinflammatory cytokines can influence the immune response locally as well as systematically, and alter the host response to photodamaged cells. We will highlight differential roles played by each IL‐1 family molecule generated by UV‐damaged keratinocytes, and reveal their complementary influences in modulating acute inflammatory and immunological events that follow cutaneous UV exposure.
UV radiation‐induced assembly of inflammasomes in keratinocytes can result in the release of different pro‐inflammatory IL‐1‐family mediators that have distinct influences on the development of the adaptive arm of cutaneous immune responses, depending on the extent of UV damage.. Precursor IL‐1β and IL‐18 cytokines require caspase‐1 activity in the inflammasome complex for their maturation and secretion. In contrast, the other IL‐1 family members, IL‐1α and IL‐33 are normally sequestered in the cell nucleus and released as “alarmins” through unconventional caspase‐1‐dependent secretion. Different DAMPs activate TLR‐induced transcription and NLR‐induced formation of inflammasomes that result in the secretion of IL‐1 family mediators that have distinct influences on different T‐cell subsets.