Psoriasiform Inflammation Is Associated with Mitochondrial Fission/GDAP1L1 Signaling in Macrophages.
Int J Mol Sci
; 22(19)2021 Sep 27.
Article
en En
| MEDLINE
| ID: mdl-34638757
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Psoriasis
/
Proteínas Mitocondriales
/
Dinámicas Mitocondriales
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Imiquimod
/
Macrófagos
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2021
Tipo del documento:
Article
País de afiliación:
Arabia Saudita