Molecular Mechanisms Behind the Role of Plasmacytoid Dendritic Cells in Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is a debilitating autoimmune disease that affects multiple systems. It is characterized by immunological deregulation, functional and structural abnormalities of small blood vessels, and fibrosis of the skin, and, in some cases, internal organs. Fibrosis has a devastating impact on a patient's life and lung fibrosis is associated with high morbimortality. Several immune populations contribute to the progression of SSc, and plasmacytoid dendritic cells (pDCs) have been identified as crucial mediators of fibrosis. Research on murine models of lung and skin fibrosis has shown that pDCs are essential in the development of fibrosis, and that removing pDCs improves fibrosis. pDCs are a subset of dendritic cells (DCs) that are specialized in anti-viral responses and are also involved in autoimmune diseases, such as SSc, systemic lupus erythematosus (SLE) and psoriasis, mostly due to their capacity to produce type I interferon (IFN). A type I IFN signature and high levels of CXCL4, both derived from pDCs, have been associated with poor prognosis in patients with SSc and are correlated with fibrosis. This review will examine the recent research on the molecular mechanisms through which pDCs impact SSc.

Keywords: CXCL4; ER stress; autoimmunity; fibrosis; plasmacytoid dendritic cells; systemic sclerosis; type I IFN.

Figure 1

The critical role of CXCL4 in the pathogenesis of SSc. CXCL4 is aberrantly secreted by pDCs in SSc [77]. It is produced upon TLR9 stimulation under hypoxic conditions [80] or upon TLR8 activation [75]. CXCL4 forms complexes with DNA, which stimulate TLR9-induced IFN-α production by pDCs [81], creating a harmful feedback loop that exacerbates pDCs innate capacity to produce high quantities of type I IFN [81,82]. Additionally, CXCL4 directly promotes differentiation of different cells into myofibroblasts, the main profibrotic cell in SSc [79]; increases the secretion of PDGF-BB by monocytes, driving fibroblasts activation [88]; alters moDC differentiation, maturation and activity [89,90]; induces T-cell proliferation [82,90]; and, by forming complexes with DNA, stimulates B cells and induces them to produce anti-CXCL4 antibodies, which can bind to CXCL4-DNA complexes and increase their activity, contributing to disease progression [82]. IFN-I: type I IFN. Created with https://biorender.com/ (accessed on 3 February 2023).

Figure 2

The role of ER stress in type I IFN production by human pDCs. (a) pDCs that are isolated from the blood of healthy donors (HDs) facing ER stress and TLR7/9 activation present an increase in the IRE1α-XBP1 pathway. In these conditions, there is upregulation of the PHGDH levels, favoring serine synthesis besides TCA cycle, reducing ATP levels, and leading to a decrease in the type I IFN production triggered by TLR activation (left). In the presence of pyruvate, the TCA cycle is potentiated, resulting in a synergy of ER stress and TLR7/9 activation and, thus, the production of high levels of type I IFN (right). (b) On the other hand, pDCs that are isolated from the blood of systemic sclerosis (SSc) patients present decreased levels of the IRE1α-XBP1 pathway. Thus, PHGDH levels are reduced compared with HDs, resulting in a pyruvate and α-ketoglutarate-mediated induction of the TCA cycle that promotes type I IFN production, contributing to the type I IFN signature observed in SSc [119]. Created with https://biorender.com/ (accessed on 3 February 2023).