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Inflammatory pain, such as hypersensitivity resulting from surgical tissue injury, occurs as a result of interactions between the immune and nervous systems with the orchestrated recruitment and activation of tissue-resident and circulating immune cells to the site of injury. Our previous studies identified a central role for Ly6Clow myeloid cells in the pathogenesis of postoperative pain. We now show that the chemokines CCL17 and CCL22, with their cognate receptor CCR4, are key mediators of this response. Both chemokines are up-regulated early after tissue injury by skin-resident dendritic and Langerhans cells to act on peripheral sensory neurons that express CCR4. CCL22, and to a lesser extent CCL17, elicit acute mechanical and thermal hypersensitivity when administered subcutaneously; this response abrogated by pharmacological blockade or genetic silencing of CCR4. Electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice showed that CCL22 was able to directly activate neurons and enhance their excitability after injury. These responses were blocked using C 021 and small interfering RNA (siRNA)-targeting CCR4. Finally, our data show that acute postoperative pain is significantly reduced in mice lacking CCR4, wild-type animals treated with CCR4 antagonist/siRNA, as well as transgenic mice depleted of dendritic cells. Together, these results suggest an essential role for the peripheral CCL17/22:CCR4 axis in the genesis of inflammatory pain via direct communication between skin-resident dendritic cells and sensory neurons, opening therapeutic avenues for its control.

Background Granulocyte macrophage-colony stimulating factor (GM-CSF) has been implicated in the pathogenesis of a number of inflammatory diseases and in osteoarthritis (OA). We identified previously a new GM-CSF→Jmjd3→interferon regulatory factor 4 (IRF4)→chemokine (c-c motif) ligand 17 (CCL17) pathway, which is important for the development of inflammatory arthritis pain and disease. Tumour necrosis factor (TNF) can also be linked with this pathway. Here we investigated the involvement of the pathway in OA pain and disease development using the GM-CSF-dependent collagenase-induced OA (CiOA) model. Methods CiOA was induced in C57BL/6 wild-type (WT), Irf4 −/− , Ccl17 E/E , Ccr4 −/− , Tnf −/− and GM-CSF −/− mice. Additionally, therapeutic targeting of CCL17, Jmjd3 and cyclooxygenase 2 (COX-2) was evaluated. Development of pain (assessment of weight distribution) and OA disease (histologic scoring of synovitis, cartilage destruction and osteophyte size) were assessed. Synovial joint cells, including neutrophils, macrophages, fibroblasts and endothelial cells, were isolated (cell sorting) and gene expression analyzed (quantitative PCR). Results Studies in the gene-deficient mice indicated that IRF4, CCL17 and the CCL17 receptor, CCR4, but not TNF, were required for CiOA pain and optimal cartilage destruction and osteophyte size. Therapeutic neutralization of CCL17 and Jmjd3 ameliorated both pain and disease, whereas the COX-2 inhibitor only ameliorated pain. In the synovium Ccl17 mRNA was expressed only in the macrophages in a GM-CSF-dependent and IRF4-dependent manner. Conclusions The GM-CSF→Jmjd3→IRF4→CCL17 pathway is important for the development of CiOA, with CCL17 thus being a potential therapeutic target for the treatment of both OA pain and disease.

Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GM-CSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo. In murine models of arthritis and pain, IRF4 regulated the formation of CCL17, which mediated the proinflammatory and algesic actions of GM-CSF. Mechanistically, GM-CSF upregulated IRF4 expression by enhancing JMJD3 demethylase activity. We also determined that CCL17 has chemokine-independent functions in inflammatory arthritis and pain. These findings indicate that GM-CSF can mediate inflammation and pain by regulating IRF4-induced CCL17 production, providing insights into a pathway with potential therapeutic avenues for the treatment of inflammatory diseases and their associated pain.

The main pathogenic factor in atopic dermatitis (AD) is Th2 inflammation, and levels of serum CCL17 and CCL22 are related to severity in AD patients. Fulvic acid (FA) is a kind of natural humic acid with anti-inflammatory, antibacterial, and immunomodulatory effects. Our experiments demonstrated the therapeutic effect of FA on AD mice and revealed some potential mechanisms. FA was shown to reduce TARC/CCL17 and MDC/CCL22 expression in HaCaT cells stimulated by TNF-α and IFN-γ. The inhibitors showed that FA inhibits CCL17 and CCL22 production by deactivating the p38 MAPK and JNK pathways. After 2,4-dinitrochlorobenzene (DNCB) induction in mice with atopic dermatitis, FA effectively reduced the symptoms and serum levels of CCL17 and CCL22. In conclusion, topical FA attenuated AD via downregulation of CCL17 and CCL22, via inhibition of P38 MAPK and JNK phosphorylation, and FA is a potential therapeutic agent for AD.

Bullous pemphigoid (BP) is a type 2 inflammation- and immunity-driven skin disease, yet a comprehensive understanding of the immune landscape, particularly immune-stromal crosstalk in BP, remains elusive. Herein, using single-cell RNA sequencing (scRNA-seq) and in vitro functional analyzes, we pinpoint Th2 cells, dendritic cells (DCs), and fibroblasts as crucial cell populations. The IL13 - IL13RA1 ligand–receptor pair is identified as the most significant mediator of immune-stromal crosstalk in BP. Notably, fibroblasts and DCs expressing IL13RA1 respond to IL13-secreting Th2 cells, thereby amplifying Th2 cell-mediated cascade responses, which occurs through the specific upregulation of PLA2G2A in fibroblasts and CCL17 in myeloid cells, creating a positive feedback loop integral to immune-stromal crosstalk. Furthermore, PLA2G2A and CCL17 contribute to an increased titer of pathogenic anti-BP180-NC16A autoantibodies in BP patients. Our work provides a comprehensive insight into BP pathogenesis and shows a mechanism governing immune-stromal interactions, providing potential avenues for future therapeutic research. Bullous pemphigoid (BP) is a type 2 immunity associated skin inflammatory disease. Here the authors characterize the underlying immune-stromal crosstalk in this disease using scRNA sequencing to show that IL13-IL13RA1 signals are involved with fibroblast and DC mediated enhancement of Th2 responses.

Eosinophil infiltration, a hallmark of allergic asthma, is essential for type 2 immune responses. How the initial eosinophil recruitment is regulated by lung dendritic cell (DC) subsets during the memory stage after allergen challenge is unclear. Here, we show that the initial eosinophil infiltration is dependent on lung cDC1s, which require nitric oxide (NO) produced by inducible NO synthase from lung CD24 − CD11b + DC2s for inducing CCL17 and CCL22 to attract eosinophils. During late phase responses after allergen challenge, lung CD24 + cDC2s inhibit eosinophil recruitment through secretion of TGF-β1, which impairs the expression of CCL17 and CCL22. Our data suggest that different lung antigen-presenting cells modulate lung cDC1-mediated eosinophil recruitment dynamically, through secreting distinct soluble factors during the memory stage of chronic asthma after allergen challenge in the mouse. Eosinophils are important mediators of allergic responses, but how they are recruited to the inflamed site is still unclear. Here the authors show that CD103 + cDC1 cells secrete CCL17 and CCL22 for eosinophil recruitment, with this process promoted by CD24 − CD11b + DC2s in the early phase but suppressed by CD24 + cDC2s in the late phase.

Signal tranducer and activator of transcription 5 (STAT5) plays a critical role in mediating cellular responses following cytokine stimulation. STAT proteins critically signal via the formation of dimers, but additionally, STAT tetramers serve key biological roles, and we previously reported their importance in T and natural killer (NK) cell biology. However, the role of STAT5 tetramerization in autoimmune-mediated neuroinflammation has not been investigated. Using the STAT5 tetramer-deficient Stat5a-Stat5b N-domain double knockin (DKI) mouse strain, we report here that STAT5 tetramers promote the pathogenesis of experimental autoimmune encephalomyelitis (EAE). The mild EAE phenotype observed in DKI mice correlates with the impaired extravasation of pathogenic T-helper 17 (Th17) cells and interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. We further demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF)–mediated STAT5 tetramerization regulates the production of CCL17 by MDCs. Importantly, CCL17 can partially restore the pathogenicity of DKI Th17 cells, and this is dependent on the activity of the integrin VLA-4. Thus, our study reveals a GM-CSF-STAT5 tetramer-CCL17 pathway in MDCs that promotes autoimmune neuroinflammation.

Background Atherosclerosis (AS) is a cardiovascular problem, which is featured by the accumulation of lipids in the intimal layer of the arterial wall and inflammatory reaction of immune cells. CCL17 is an inflammatory mediator associated with promoting AS. Nevertheless, the specific role of CCL17 and its upstream regulatory mechanisms in macrophage mediated inflammation and AS remain unclear. Methods An AS mice model was established by subjecting ApoE −/− mice to a high-fat diet (HFD). Constructing an AS cell model by treating primary macrophages with oxidized low-density lipoprotein (ox LDL). Injecting shRNA wrapped by AAV virus into the tail vein of mice knocked down CCL17 and SENP3 in mice. Hematoxylin–eosin (HE) and oil red O staining were used to detect arterial injury in mice. The changes of Treg cells were detected by flow sorting. Cycloheximide (CHX) and immunoprecipitation were used to detect the level of DeSUMOylation of CCL17 modified by SENP3. Results The CCL17 and SENP3 expression in plaque sample of AS mice were significantly up-regulated. Knocking down CCL17 or SENP3 in mice could reverse the vascular damage, lipid accumulation, the increase of the blood lipid levels and the increase of inflammatory reaction in AS mice. On the molecular mechanism level, SENP3 increased the protein stability of CCL17 and thus increased CCL17 expression by DeSUMOylation modification at K115 site of CCL17 protein. In macrophages induced by oxLDL, CCL17 and CCL22 affect the chemotaxis of Treg competitively. Conclusion This study showed that SENP3 mediated deSUMOylation of CCL17, increase CCL17 expression in macrophage. CCL17 secreted by macrophage regulating Treg recruitment through the competitive interaction between CCL17 and CCL22 and thus aggravated AS. Our findings provide a new regulatory mechanism and potential target for AS treatment. Graphical Abstract Highlights 1. CCL17 and SENP3 expression in plaque tissue of AS mice were increased. 2. Knocking down CCL17 or SENP3 improved the progress of AS. 3. The stability of CCL17 protein is regulated by SENP3-mediated DeSUMOylation. 4. Macrophages stimulated by ox-LDL affect the chemotaxis of Treg through CCL17 and CCL22 competition.

Rheumatoid arthritis (RA) is an inflammatory and destructive autoimmune polyarthritis that causes pain, swelling and deformity in the joints. While clinical trials targeting GM-CSF in RA are showing promise, the potential side effects of anti-GM-CSF therapy highlight the need for identifying downstream mediators of GM-CSF action. CCL17, a downstream inflammatory mediator of GM-CSF in monocytes and macrophages, has been shown to mediate GM-CSF-driven inflammatory arthritis in animal models. CCL17 shares its receptor, CCR4, with CCL22; however, unlike CCL17, CCL22 has been implicated in resolving inflammation. Therefore, drugs that can suppress the formation of CCL17, but not CCL22, may be beneficial in the treatment of inflammatory arthritis. In this study, we screened a panel of 1508 FDA-approved drugs and identified five drugs, namely fluoxetine, ractopamine, ponesimod, terbutaline and etravirine, which potently inhibited CCL17 production without adverse effects on cell viability and CCL22 formation in human monocytes and mouse macrophages. Mechanistically, we demonstrated that these drugs inhibited STAT5 activity and IRF4 expression to suppress CCL17 formation. Significantly, therapeutic administration of these five drugs in an inflammatory arthritis model revealed that fluoxetine, ractopamine, ponesimod and terbutaline could inhibit arthritic pain, correlating with decreased CCL17 expression. Given the need for new and safe anti-inflammatory therapeutics to treat RA and the benefits of repurposing existing drugs for new indications, our findings reported here offer four new promising analgesics for treating inflammatory pain.

The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells and mice we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. airway epithelial cell- and mouse-RV infection models were then used to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface-differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-κB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.