Abstract
While psoriasis is known as a T cell- and dendritic cell-driven skin inflammation disease, macrophages are also reported to play some roles in its development. However, the signaling pathway of activated macrophages contributing to psoriasis is not entirely understood. Thus, we aimed to explore the possible mechanisms of how macrophages initiate and sustain psoriasis. The differentiated THP1 cells, stimulated by imiquimod (IMQ), were utilized as the activated macrophage model. IMQ was also employed to produce psoriasis-like lesions in mice. A transcriptomic assay of macrophages revealed that the expressions of pro-inflammatory mediators and GDAP1L1 were largely increased after an IMQ intervention. The depletion of GDAP1L1 by short hairpin (sh)RNA could inhibit cytokine release by macrophages. GDAP1L1 modulated cytokine production by activating the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways. Besides GDAP1L1, another mitochondrial fission factor, Drp1, translocated from the cytosol to mitochondria after IMQ stimulation, followed by the mitochondrial fragmentation according to the immunofluorescence imaging. Clodronate liposomes were injected into the mice to deplete native macrophages for examining the latter’s capacity on IMQ-induced inflammation. The THP1 cells, with or without GDAP1L1 silencing, were then transplanted into the mice to monitor the deposition of macrophages. We found a significant THP1 accumulation in the skin and lymph nodes. The silencing of GDAP1L1 in IMQ-treated animals reduced the psoriasiform severity score from 8 to 2. After depleting GDAP1L1, the THP1 recruitment in the lymph nodes was decreased by 3-fold. The skin histology showed that the GDAP1L1-mediated macrophage activation induced neutrophil chemotaxis and keratinocyte hyperproliferation. Thus, mitochondrial fission can be a target for fighting against psoriatic inflammation.
Highlights
One of the most widespread autoimmune cutaneous disorders is psoriasis
We selected the differentially expressed coding genes (DEGs) commonly involved in psoriatic pathogenesis for showing the heatmap (Figure 1a)
The experimental results in this study suggested that infiltration and activation of macrophages were necessary to establish psoriasiform inflammation
Summary
One of the most widespread autoimmune cutaneous disorders is psoriasis. This disease affects 0.5–11% of the global population, depending on geographic distribution, age, and ethnicity [1]. The associated comorbid diseases include cardiovascular disorders, metabolic syndromes, lymphoma, and mental illness [3]. Psoriasis is considered a disease predominantly mediated by T cells and dendritic cells [4]. CD3+ T lymphocytes and CD11c+ dendritic cells are reported to play a vital role in psoriatic pathogenesis [5]. There is increasing evidence showing the key role of macrophages in the development of psoriatic lesion [6]. Macrophages are largely found to release cytokines and chemokines in the early lesional site of psoriasis [7]
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