Antimicrobial Peptides: Bridging Innate and Adaptive Immunity in the Pathogenesis of Psoriasis
Psoriasis is a chronic autoimmune skin disorder characterized by aberrant immune responses involving T cells, keratinocytes, and dendritic cells (DCs). The pathogenesis of psoriasis is complex, with both innate and adaptive immune systems playing critical roles. Among the key players in this process are antimicrobial peptides (AMPs), small molecules produced by various cells that not only protect against infections but also contribute to immune dysregulation under pathological conditions. This article explores the roles of AMPs in psoriasis, focusing on their immunomodulatory functions and their potential as therapeutic targets.
Introduction to Antimicrobial Peptides
AMPs are integral components of the host’s first-line defense against pathogens. These peptides are typically amphipathic, with α-helical structures or β-sheets stabilized by disulfide bridges. Initially discovered for their bactericidal effects, AMPs are secreted by immune cells, epithelial cells, and keratinocytes in response to stimuli such as injury, infections, and mechanical stress. Beyond their antimicrobial properties, AMPs regulate immune responses, chemotaxis, wound healing, apoptosis, and angiogenesis. In psoriasis, AMPs are highly expressed in skin lesions and play a significant role in linking innate and adaptive immunity.
AMPs in Psoriasis: Key Players and Mechanisms
Several AMPs, including cathelicidin (LL-37), human β-defensins (hBDs), S100 proteins, lipocalin 2 (LCN2), and RNase 7, are overexpressed in psoriatic skin lesions. These peptides interact with various immune cells, including keratinocytes, neutrophils, macrophages, and DCs, to initiate and sustain the inflammatory cascade characteristic of psoriasis.
Cathelicidin (LL-37)
LL-37, the only human cathelicidin, is a 37-amino acid peptide encoded by the CAMP gene. It forms pores on microbial membranes, limiting microbial adhesion and proliferation. In psoriasis, LL-37 levels are elevated in skin lesions and correlate with disease activity. LL-37 expression in keratinocytes is promoted by cytokines such as IL-17A and TNF-α. Following skin injury, LL-37 is rapidly induced, contributing to the Koebner phenomenon, where psoriatic lesions appear after physical trauma.
LL-37 binds to DNA and RNA released from injured cells, forming complexes that stimulate plasmacytoid dendritic cells (pDCs) via toll-like receptor (TLR) 9. This interaction triggers the production of IFN-α, which activates myeloid dendritic cells (mDCs) and autoreactive T cells, initiating an adaptive immune response. LL-37 also directly activates mDCs and keratinocytes through TLR9/3 signaling. Additionally, LL-37 interacts with RNA derived from neutrophil extracellular traps (NETs), promoting cytokine release and NET formation via the TLR8/TLR13 pathway.
LL-37 regulates keratinocytes by inducing the production of cytokines and chemokines such as IFNs, IL-36γ, and CXCLs. It also suppresses apoptosis and enhances epidermal barrier function. As an autoantigen, LL-37 activates T cells involved in the IL-23/Th17 axis. Patients with psoriasis develop LL-37-specific CD4+ and CD8+ T cells that infiltrate skin lesions and produce IFN-γ and Th17 cytokines. LL-37 also interacts with the PSORS locus HLA-C∗06:02 allele, forming a complex that activates T cells via the T cell receptor.
Human β-Defensins (hBDs)
hBDs are small cationic polypeptides with potent antimicrobial activity. Among the six identified hBDs, hBD-2 and hBD-3 are extensively studied in psoriasis. These peptides are expressed in keratinocytes and epithelial cells and are modulated by cytokines such as IL-17A, IL-22, and NETs.
hBD-2 and hBD-3 induce keratinocyte proliferation and the secretion of proinflammatory cytokines and chemokines such as IL-6, IL-10, and CCL5. hBD-3 also induces the expression of IL-37, an immunosuppressive cytokine, in keratinocytes. Both hBD-2 and hBD-3 promote the uptake of self-DNA or CpG DNA by pDCs, enhancing IFN-α production. hBD-3 activates mDCs via TLR1/2 and promotes IL-23 production by epidermal Langerhans cells (LCs), exacerbating psoriasis-like skin inflammation.
Clinically, the genomic copy number of β-defensin genes is associated with an increased risk of psoriasis. hBDs also affect the homeostasis of the skin microbiome, suggesting a microbiota-associated role in psoriatic inflammation.
S100 Proteins
S100 proteins are calcium-binding molecules encoded in the psoriasis susceptibility locus on chromosome 1q21. S100A4, S100A7, S100A8/A9, S100A12, and S100A15 are highly expressed in psoriatic skin lesions and serum. These proteins are secreted by keratinocytes, neutrophils, monocytes/macrophages, and dermal DCs in response to proinflammatory cytokines and TLR/RAGE signaling.
S100 proteins regulate keratinocytes by inducing the expression of psoriasis-associated cytokines such as IL-1α, IL-23, and MIP-2. S100A8/A9 stimulates the production of IL-8, CXCL1, CXCL2, and CCL20, contributing to psoriatic inflammation. These proteins also promote keratinocyte proliferation and abnormal differentiation, leading to hyperkeratosis and parakeratosis. S100A8 and S100A9 recruit and activate neutrophils, accelerating neutrophil infiltration in psoriatic lesions. They also promote the development of autoreactive CD8+ T cells, linking inflammation and autoimmunity.
S100 proteins are associated with psoriasis-related comorbidities such as psoriatic arthritis, Crohn disease, metabolic syndrome, and cardiovascular disorders. Elevated serum levels of S100A8/A9 and S100A12 are potential biomarkers of disease severity in psoriatic arthritis.
Lipocalin 2 (LCN2)
LCN2, also known as neutrophil gelatinase-associated lipocalin, is a glycoprotein involved in inflammatory processes and metabolic diseases. In psoriasis, LCN2 is secreted by keratinocytes stimulated with IL-17A, IL-22, and TNF-α, as well as by infiltrated neutrophils. LCN2 induces chemotaxis and cytokine secretion in neutrophils via the 24p3R receptor and downstream p38-MAPK and ERK-1/2 signaling pathways. Neutralization of LCN2 attenuates disease severity and inflammatory infiltration in mouse models of psoriasis.
LCN2 is associated with chronic itch in inflammatory skin diseases, acting as a downstream effector of astrocytic STAT3 signaling. It also modulates lipid metabolism pathways, contributing to comorbid diseases such as metabolic syndrome, cardiovascular disease, and non-alcoholic fatty liver disease.
RNase 7
RNase 7, a member of the RNase A superfamily, is an AMP abundant in keratinocytes and epithelial cells. It is rapidly induced by skin injury and is overexpressed in psoriatic skin lesions. RNase 7 promotes the sensing of self-DNA by pDCs and keratinocytes via TLR regulation, similar to LL-37 and hBDs. Interestingly, RNase 7 suppresses the production of Th2 cytokines (IL-13, IL-4, and IL-5) in CD4+ T cells, independent of its ribonuclease activity.
AMPs as Biomarkers and Therapeutic Targets
AMPs have clinical relevance in psoriasis and may serve as biomarkers for disease activity and treatment response. For example, AMP levels are downregulated by narrowband ultraviolet B (NB-UVB) therapy and vitamin D analogs. Biotherapies targeting the IL-23/IL-17 axis, such as secukinumab, risankizumab, and ustekinumab, reduce the production of hBD-2 and LCN2 in psoriatic skin lesions. Tasquinimod, an S100A9 inhibitor, has shown promise in clinical trials for other inflammatory conditions, suggesting potential applications in psoriasis treatment.
Challenges and Future Directions
Despite the significant progress in understanding the roles of AMPs in psoriasis, several challenges remain. For instance, while LL-37 is a well-studied autoantigen in psoriasis, it is unclear whether other AMPs, such as LCN2 and S100 proteins, share similar properties. Additionally, the dual roles of LL-37 in promoting inflammation and protecting against infections require further investigation. The interplay between AMPs and pattern recognition receptors (PRRs) also warrants deeper exploration to elucidate their immunomodulatory mechanisms.
Moreover, the potential of AMPs as therapeutic targets must be carefully evaluated. While targeting AMPs may offer new avenues for psoriasis treatment, their antimicrobial properties and dynamic bioactivity must be considered to ensure safety and efficacy.
Conclusion
AMPs play a pivotal role in the pathogenesis of psoriasis by bridging innate and adaptive immune responses. They act as alarmins, autoantigens, and immunomodulators, contributing to the inflammatory cascade and disease progression. As biomarkers and therapeutic targets, AMPs hold promise for advancing the understanding and treatment of psoriasis. Continued research into the characteristics and interactions of AMPs will provide valuable insights into the complex mechanisms underlying psoriasis and pave the way for innovative therapeutic strategies.
doi.org/10.1097/CM9.0000000000001240
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