Research based on serine metabolism indicates mesenchymal stem cells alleviate psoriasis by regulating the PSPH-PINK1-Parkin-NLRP3 pathway in HaCaT

Abstract

Background: Psoriasis is a refractory immune-related disease. In recent years, it has been discovered that mesenchymal stem cells (MSCs) can be used as a new therapeutic approach for psoriasis, but their potential therapeutic mechanism remains unclear. This study aims to explore the role of MSCs in the treatment of psoriasis. Methods: We employed a mouse psoriasis model induced by imiquimod (IMQ) in vivo and a co-culture system of MSCs and HaCaT keratinocytes (KCs) cell line in vitro. These approaches allowed us to investigate the effect of MSCs on the levels of inflammatory factors and the activation of inflammasomes in both contexts. Mouse-targeted amino acid sequencing, transmission electron microscopy for in vitro observation, immunofluorescence for both in vivo and in vitro analyses, and siRNA transfection in vitro were employed in this study. Results: Our results showed that MSCs significantly improved the skin lesion of mice with psoriasis, and reduced the levels of inflammatory factors and chemokines including IL-1β, IL-6, IL-8, TNF-α, MCP-1, CCL7, CCL20 and CCL27 in the mouse skin lesion areas and M5-induced psoriatic KCs models in vitro. Likewise, MSCs repaired the skin barrier by enhancing claudin-1 expression in vivo. In addition, MSCs increased KRT1 and decreased KRT6 levels in vivo and in vitro. Amino acid metabolism analysis showed that MSCs could improve the serine metabolism level in the mouse skins and upregulated the key enzyme phosphoserine phosphatase (PSPH) in serine metabolism. In vitro experiments demonstrated that knockdown of PSPH could reverse the therapeutic effects of MSCs on psoriasis. Furthermore, studies in vitro and in vivo revealed that MSCs can activate the PINK1-Parkin pathway. It was specifically manifested by elevated levels of PINK1, Parkin, p-Parkin, Beclin-1, and LC3B-II/I, coupled with a reduction in P62 protein. Subsequently, the activation of PINK1-Parkin led to decreased expressions of IL-1β, IL-6, IL-8, TNF-α, CCL7, CCL20, CCL27, and MCP-1. In vitro and in vivo experiments indicated that MSCs can reduce the levels of these inflammatory factors by inhibiting the activation of NLRP3 inflammasomes. Meanwhile, PSPH knockdown in vitro can reverse the activating effects of MSCs on the PINK1-Parkin, as shown by decreased levels of PINK, Parkin, p-Parkin, Beclin-1, and LC3B-II/I, concurrently with an elevation in P62. Conclusions: The results of this study indicated that MSCs can alleviate IMQ-induced psoriasiform dermatitis in mice by upregulating serine metabolism. The key serine metabolism enzyme PSPH may enhance PINK1/Parkin-mediated mitochondrial autophagy in psoriatic HaCaT and inhibit NLRP3 inflammasome activation in HaCaT cells, thereby alleviating skin inflammatory responses and suppressing skin proliferation in psoriatic mice.

1. Introduction

Psoriasis is a chronic inflammatory skin disease that affects approximately 2–3% of the global population [1]. It is characterized by recurrent autoimmune responses, which result in excessive hyperproliferation and aberrant differentiation of KCs [2, 3]. The prevailing hypothesis suggests that the stimulation of inflammatory factors leads to the hyperproliferation of KCs, which subsequently promotes the secretion of pro-inflammatory cytokines, exacerbating the inflammatory response [4–6]. Consequently, psoriatic KCs play a central role in the inflammatory pathogenic loop of psoriasis, functioning both as triggers of immune responses and as pro-inflammatory effectors [7]. Immunomodulatory drugs have shown some success in treating psoriasis [8]. Biologic therapies directed against TNF-α, IL-17, and IL-23 have been introduced, demonstrating considerable clinical efficacy. Nevertheless, treatment with these agents is associated with a susceptibility to disease recurrence and potential adverse effects, including nasopharyngitis, upper respiratory tract infections, and tuberculosis [9]. These limitations underscore the pressing need to develop safer alternative therapeutic strategies for psoriasis management.

MSCs are multipotent progenitor cells capable of modulating immune responses [10, 11]. Interestingly, their immunomodulatory properties can be enhanced by inflammatory cytokines [12, 13]. Thus, MSCs exhibit significant anti-inflammatory abilities in inflammatory microenvironments and are commonly used to treat psoriasis. Several case reports have documented the therapeutic effects of MSC treatment for psoriasis [14, 15]. For example, adipose-derived MSCs were utilized for one patient with psoriasis vulgaris and another with psoriatic arthritis. The patients' Psoriasis Area Severity Index (PASI) scores of the patients decreased (from 21.6 to 9.0 and 24.0 to 8.3, respectively) after multiple MSCs infusions, with no serious adverse events reported [16]. Given their easy accessibility, multipotency, and active paracrine activity, adipose-derived MSCs have emerged as the preferred MSC type for immunotherapy [17]. Therefore, adipose-derived MSCs were adopted in our current study. Nevertheless, the anti-inflammatory mechanisms of MSCs in psoriatic KCs remain poorly understood.