Inflammasome activation of IL-1 family mediators in response to cutaneous photodamage

Abstract

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.

Figure 1

A. The inflammasome. The ligand binding scaffold subtypes bind their cognate agonist (DAMPS or PAMPs) that promotes heptameric oligomerization and multimeric assembly. Subfamilies are definded by domain structure and binding partner proteins. AIM2 (Absent In Melanoma 2); ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; CARD, caspase activation and recruitment domain; Casp1, enzymatically active caspase-1; dsDNA, double stranded deoxyribonucleic acid; IL-18, interleukin-18; IL-1β, interleukin-1β; LMP, lysosomal membrane permeablization; MDP,muramyl dipeptide; NLRC4, NLR family CARD domain-containing protein 4; NLRP1, NOD-like receptor family, pyrin domain containing 1; NLRP3, NOD-like receptor family, pyrin domain containing 3; pro-Casp1, procaspase-1; PYD, pyrin domain; ROS, reactive oxygen species; ssRNA, single stranded ribonucleic acid. B. The ligand binding scaffold subtypes bind their cognate agonist (DAMPS or PAMPs) which promotes heptameric oligomerization, multimeric assembly and ultimately activation of an active caspase-1 platform. The active caspase-1 platform is required to process pro-IL-1β and pro-IL-18 into their mature forms and secrete them into extracellular space. The inflammasome is also associated with unconventional secretion of alarmins IL-1α, IL-33 and HMGB-1.

Figure 1

A. The inflammasome. The ligand binding scaffold subtypes bind their cognate agonist (DAMPS or PAMPs) that promotes heptameric oligomerization and multimeric assembly. Subfamilies are definded by domain structure and binding partner proteins. AIM2 (Absent In Melanoma 2); ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; CARD, caspase activation and recruitment domain; Casp1, enzymatically active caspase-1; dsDNA, double stranded deoxyribonucleic acid; IL-18, interleukin-18; IL-1β, interleukin-1β; LMP, lysosomal membrane permeablization; MDP,muramyl dipeptide; NLRC4, NLR family CARD domain-containing protein 4; NLRP1, NOD-like receptor family, pyrin domain containing 1; NLRP3, NOD-like receptor family, pyrin domain containing 3; pro-Casp1, procaspase-1; PYD, pyrin domain; ROS, reactive oxygen species; ssRNA, single stranded ribonucleic acid. B. The ligand binding scaffold subtypes bind their cognate agonist (DAMPS or PAMPs) which promotes heptameric oligomerization, multimeric assembly and ultimately activation of an active caspase-1 platform. The active caspase-1 platform is required to process pro-IL-1β and pro-IL-18 into their mature forms and secrete them into extracellular space. The inflammasome is also associated with unconventional secretion of alarmins IL-1α, IL-33 and HMGB-1.

Figure 2

Downstream effects of UV on inflammasome assembly and secretion of cytokines. UV activates many alarmins which in turn activate the assembly of these inflammasome complexes and required for pro-inflammatory cytokine secretion.

Figure 3

The role of IL-1 family cytokines in UVR-induced inflammation and immunosuppression. These cytokines affect different cell subtypes of innate and adaptive immunity and skew the immune system to favor activation, inflammation or tolerance.