Therapeutic Development Based on the Immunopathogenic Mechanisms of Psoriasis

Abstract

Psoriasis, a complex inflammatory autoimmune skin disorder that affects 2-3% of the global population, is thought to be genetically predetermined and induced by environmental and immunological factors. In the past decades, basic and clinical studies have significantly expanded knowledge on the molecular, cellular, and immunological mechanisms underlying the pathogenesis of psoriasis. Based on these pathogenic mechanisms, the current disease model emphasizes the role of aberrant Th1 and Th17 responses. Th1 and Th17 immune responses are regulated by a complex network of different cytokines, including TNF-α, IL-17, and IL-23; signal transduction pathways downstream to the cytokine receptors; and various activated transcription factors, including NF-κB, interferon regulatory factors (IRFs), and signal transducer and activator of transcriptions (STATs). The biologics developed to specifically target the cytokines have achieved a better efficacy and safety for the systemic management of psoriasis compared with traditional treatments. Nevertheless, the current therapeutics can only alleviate the symptoms; there is still no cure for psoriasis. Therefore, the development of more effective, safe, and affordable therapeutics for psoriasis is important. In this review, we discussed the current trend of therapeutic development for psoriasis based on the recent discoveries in the immune modulation of the inflammatory response in psoriasis.

Keywords: Toll-like receptor; anti-psoriasis drugs; autoimmune; skin inflammation; therapeutic antibody.

Figure 1

The schematic view of the inflammatory responses mediated by NF-κB activation and regulated by cAMP. Signal transductions activated by TLR agonists, TNF-α, IL-1, IL-17, and IL-36, resulting in the phosphorylation of IKKβ and formation of IKK complex. The activated IKK complex promotes the phosphorylation, ubiquitination, and subsequent proteasomal degradation of IκB, resulting in the translocation of NF-κB to the nucleus to promote the transcription of various NF-κB-controlled inflammatory cytokine genes. AC, activated by GPCRs, increases intracellular cAMP. The accumulated cAMP activates PKA, interfering with IκB ubiquitination and degradation by blocking the formation of IKK complex. PKA also activates CREB/ATF1 and increases the transcription of anti-inflammatory cytokine genes. Moreover, cAMP activates exchange protein directly activated by cAMP (Epac), regulating Ras-related protein (Rap)1 and reducing inflammatory responses. PDE 4 degrades cAMP into 5′-AMP that reduces the inhibition of the NF-κB activation by cAMP.

Figure 2

Toll-like receptor signaling pathways. TLRs 1, 2, 4, 5, and 6 localize to the cell surface, and TLRs 3, 7, 8, and 9 localize to intracellular vesicles, such as endosomes, where they recognize their ligands, including exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). The TLRs use the adaptor proteins of the MyD88 family, including MyD88, TRIF, TIRAP, and TRAM, to initiate downstream signaling pathways, leading to the activation of various transcription factors, including IRF3/7 and NF-κB, and the production of type I interferons and pro-inflammatory cytokines.

Figure 3

TNF-α and IL-17 cooperate to promote the production of pro-inflammatory cytokines. The activation of TNFR induces the production of pro-inflammatory cytokines by recruiting TRADD, TTRAF2 and 5, and RIP1 to the receptor, thus activating the IKK complex and NF-κB. IL-17 receptor (IL-17R) signaling can also induce NF-κB via ACT1 and TRAF6. Furthermore, IL-17R initiates mRNA stabilization signaling through the IKKε-mediated phosphorylation of ACT1, which binds to TRAF2 and 5 to activate mRNA binding proteins to increase mRNA instability. The combination of TNFR and IL-17R activations often results in a synergistic inflammation that can be partially explained by increased mRNA expression and stabilization.

Figure 4

JAK-STAT signaling pathways of different cytokines for initiation of T helper responses. Different combinations of JAKs are activated by different cytokine receptors to promote the phosphorylation and dimerization of different STAT proteins as illustrated. The dimerized STATs translocate to the nucleus to activate the transcription of target genes and initiate different Th responses as illustrated.

Figure 5

A model for the pathogenesis of psoriasis. In the initial stage of psoriasis, environmental stress, such as skin damage and infection, causes the release of damage-associated molecular patterns (DAMPs), such as self-RNA and self-DNA. Antimicrobial peptides (AMPs), such as LL-37 released from keratinocytes, can bind to these self-nucleic acids, inducing innate immune responses in the psoriatic lesions. The LL-37/DNA complex activates TLR7 and TLR9 in plasmacytoid dendritic cells (pDCs) to release pro-inflammatory cytokines and type I IFNs, which activate the maturation of myeloid dendritic cells (mDCs). LL37/RNA complexes can also activate TLR8 in mDCs to produce IL-12 and IL-23. Moreover, the polarization of macrophages into the M1 subset can be activated to produce pro-inflammation cytokines at this stage. In the development phase of psoriasis, adaptive immune responses are activated and psoriatic inflammation is amplified. The cytokines in the psoriatic lesions activate Th1 and Th17 cells for production of various cytokines to contribute to the inflammatory milieu and act on keratinocytes. The keratinocytes are then activated to produce inflammatory cytokines, chemokines, and AMPs to recruit leukocyte infiltrates and activations, forming a self-amplifying feedback loop in the psoriatic inflammatory response.