# Roles for Exosomes in the Pathogenesis, Drug Delivery and Therapy of Psoriasis
## 3 The Immunological Function of Exosomes That Are or Are Not Associated with Soriasis
### Non-Immune Cell-Derived Exosomes
#### 3.2.3 Fibroblast-Derived Exosomes  
Fibroblasts promote wound healing and maintain the integrity of the skin by producing growth factors and extracellular matrix (ECM) components. However, recent studies have revealed that fibroblasts are involved in the pathogenesis of psoriasis. For example, an inflammation-induced subset of papillary fibroblasts promoted aberrant neurite outgrowth and psoriasisiform skin inflammation by secreting the ECM protein tenascin-C (TNC) [79]. Additionally, a single cell and spatial sequencing study demonstrated that a subset of SFRP2\({}^{+}\) fibroblasts in the context of psoriasis contributed to amplification of the immune network through transition to a proinflammatory state. The SFRP2\({}^{+}\) fibroblasts also expressed cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes [80]. A recent study found that DC-secreted LGALS9 was received by CD44\({}^{+}\) dermal fibroblasts, resulting in an increase in ECM expression and basal epidermal cell hyperproliferation in psoriatic skin [81]. Fibroblasts were also involved in the recurrence of psoriasis. [PERSON] et al. found that MMP2\({}^{\text{hi}}\) fibroblasts amplified psoriatic inflammation through the CD100-PLXNB2 axis and upregulated CD103 expression in CD8\({}^{+}\) T cells, thereby enhancing the tissue residency of CD8\({}^{+}\) T cells [82]. Fibroblast-derived exosomes may also dually regulate keratinocytes. A previous study reported that exosomes derived from senescent fibroblasts accelerated the closure of epidermal keratinocytes and impaired keratinocyte differentiation in vitro [47]. On the other hand, dermal fibroblast-derived exosomes inhibited epidermal hyperplasia and increased the levels of filaggrin and hyaluronic acid synthase 1 (HAS1) by augmenting the expression of peroxisome proliferatorator-activated receptor \(\alpha\) (PPAR\(\alpha\)) in HaCaT cells [48]. However, it remains unclear how fibroblast-derived exosomes exactly impact psoriasis. In conclusion, exosomes secreted by either immune or non-immune cells have a variety of immunomodulatory functions, including antigen presentation, cell proliferation and differentiation and pro-inflammatory responses. Among them, exosomes derived from neutrophils, macrophage, mast cells, T cells and keratinocytes are involved in the pathophysiological processes of psoriasis, as shown in Figure 1. In brief, the exosomes from neutrophils or macrophages promoted the secretion of inflammatory cytokines and abnormal proliferation in keratinocytes, respectively. Keratinocyte-derived exosomes, in turn, increased the release of NETs by neutrophils and promoted proliferation and M1 polarization of macrophages. Keratinocyte-derived exosomes also promoted T cell differentiation into Th1/Th17 cells in the context of psoriasis. Additionally, mast cell-derived exosomes activated T cells to produce IL-17A and IL-22, while T cell exosomes in turn stimulated mast cells to release IL-24 in the psoriatic skin lesions. Figure 1: Exosome-mediated communication between immune cells and keratinocytes contributes to the development of psoriasis. Neutrophil-derived exosomes containing olfactomedin 4 (OLFM4) increase the expression of IL-19, IL-36G, IL-18, TNF-\(\alpha\) and CCLs in keratinocytes by activating MAPK  
and NF-kB pathways. Macrophage-derived exosomes enhance the asymmetric division of basal stem cells by activating the Par3/mInsc/LGN signaling pathway. Mast cell exosomes transfer phospholipase A2 (PLA2) to CD1a-reactive T cells from psoriaticatie patients, inducing the production of IL-17A and IL-22. T cell-derived exosomes stimulate mast cells to degranulate and release IL-24, which in turn activates keratinocytes. Keratinocyte-derived exosomes containing miR-381-3p promote T cell differentiation into Th1/Th17 cells under psoriaticatie conditions.