S1PR4‐dependent CCL2 production promotes macrophage recruitment in a murine psoriasis model

Abstract

The sphingolipid sphingosine‐1‐phosphate (S1P) fulfills distinct functions in immune cell biology via binding to five G protein‐coupled receptors. The immune cell‐specific sphingosine‐1‐phosphate receptor 4 (S1pr4) was connected to the generation of IL‐17‐producing T cells through regulation of cytokine production in innate immune cells. Therefore, we explored whether S1pr4 affected imiquimod‐induced murine psoriasis via regulation of IL‐17 production. We did not observe altered IL‐17 production, although psoriasis severity was reduced in S1pr4‐deficient mice. Instead, ablation of S1pr4 attenuated the production of CCL2, IL‐6, and CXCL1 and subsequently reduced the number of infiltrating monocytes and granulocytes. A connection between S1pr4, CCL2, and Mϕ infiltration was also observed in Zymosan‐A induced peritonitis. Boyden chamber migration assays functionally linked reduced CCL2 production in murine skin and attenuated monocyte migration when S1pr4 was lacking. Mechanistically, S1pr4 signaling synergized with TLR signaling in resident Mϕs to produce CCL2, likely via the NF‐κB pathway. We propose that S1pr4 activation enhances TLR response of resident Mϕs to increase CCL2 production, which attracts further Mϕs. Thus, S1pr4 may be a target to reduce perpetuating inflammatory responses.

2,4-Dimethoxy-6-Methylbenzene-1,3-diol, a Benzenoid From Antrodia cinnamomea, Mitigates Psoriasiform Inflammation by Suppressing MAPK/NF-κB Phosphorylation and GDAP1L1/Drp1 Translocation

“…CC chemokines majorly recruit T cells and monocytes, whereas CXC chemokines predominantly recruit neutrophils in psoriasis (34). For instance, enhanced CCL2 release by macrophages induces monocyte migration to the psoriasiform lesions in mice (35). CCL4L2 and CCL22 are pivotal chemokines in patients with psoriasis to stimulate the chemotactic infiltration of dendritic cells and macrophages (36,37).…”

Investigation on the Mechanism of Qubi Formula in Treating Psoriasis Based on Network Pharmacology

“…At present, the widely acknowledged histopathological features of psoriasis include four major aspects: the inflammatory infiltration in dermis and epidermis, the abnormal biological behaviours (differentiation, hyperproliferation, and apoptosis) of keratinocytes, metabolic disturbance in skin tissue, and the tortuously increased dermal blood vessels and capillaries [37][38][39][40][41]. Firstly, among the 27 core targets, most of them (PTGS2, ILs, JAK2, STAT3, RELA, CCL2, CXCL8, EGF, IFNG, and TLR4) have been shown to be involved in abnormal inflammatory infiltration, which could regulate the differentiation and chemotaxis of lymphocytes, cytokines produced, and immunological inflammatory reaction in dermis and epidermis [42][43][44][45][46][47][48]. Secondly, RELA, MAPKs, JUN, and BCL2L1 are associated with the aberrant biological behaviours of keratinocytes in psoriasis [49][50][51].…”

Putative Genes and Pathways Involved in the Acne Treatment of Isotretinoin via Microarray Data Analyses

“…CCL2 , namely, C-C Motif Chemokine Ligand 2, is a chemotactic factor which attracts monocytes and basophils but not for neutrophils or eosinophils and involves in immunoregulatory and inflammatory processes. A study of Schuster et al showed that S1pr4 activation increases CCL2 production which promotes macrophage infiltration in a murine psoriasis model [ 14 ]. TNF signaling pathway involves in a wide range of biological processes including cell survival, apoptosis, immunity, and inflammation.…”