Interleukin‐33 (IL‐33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL‐33 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL‐33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2−/− substantially reduced scratching behaviors in 2,4‐dinitrofluorobenzene (DNFB)‐induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water‐induced dry skin in mice. Intrathecal administration of the neutralizing anti‐ST2 or anti‐IL‐33 antibody remarkably decreased the scratching response in DNFB‐induced ACD mice. Expression of spinal IL‐33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL‐33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2−/−. Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL‐33 pretreatment exacerbated gastrin‐releasing peptide (GRP)‐evoked scratching behaviors. This increased gastrin‐releasing peptide receptor (GRPR) expression was abolished by St2−/−. Tnf‐α upregulation was suppressed by St2−/−. Our results indicate that the spinal IL‐33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2‐STAT3 cascade activation, promoting TNF‐α release to regulate the GRP/GRPR signaling‐related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.
Interleukin-4 (IL-4) has been considered as one of the tolerogenic cytokines in many autoimmune animal models and clinical settings. Despite its role in antagonizing pathogenic Th1 responses, little is known about whether IL-4 possesses functions that affect regulatory T cells (Tregs). Tregs are specialized cells responsible for the maintenance of peripheral tolerance through their immune modulatory capabilities. Interestingly, it has been suggested that IL-4 supplement at a high concentration protects responder T cells (Tresps) from Treg-mediated immune suppression. In addition, such supplement also impedes TGF-β-induced Treg differentiation in vitro. However, these phenomena may contradict the tolerogenic role of IL-4, and the effects of IL-4 on Tregs are therefore needed to be further elucidated. In this study, we utilized IL-4 knockout (KO) mice to validate the role of IL-4 on Treg-mediated immune suppression. Although IL-4 KO and control animals harbor similar frequencies of Tregs, Tregs from IL-4 KO mice weakly suppressed autologous Tresp activation. In addition, IL-4 deprivation impaired the ability of Tregs to modulate immune response, whereas IL-4 supplementation reinforced IL-4 KO Tregs in their function in suppressing Tresps. Finally, the presence of IL-4 was associated with increased cell survival and granzyme expression of Tregs. These results suggest the essential role of IL-4 in supporting Treg-mediated immune suppression, which may benefit the development of therapeutic strategies for autoimmune diseases.
Daily subcutaneous (sc) injection of bleomycin (BLM) causes dermal fibrosis but rarely causes lung changes in mice. There are also significant disadvantages to this traditional model for systemic sclerosis, including a variable distribution of lesions and a requirement for repetitive procedures. The present study was undertaken to develop a convenient method of BLM administration that yields stable dermal inflammation and fibrosis with extensive and reproducible interstitial lung disease (ILD) in mice. Osmotic minipumps containing BLM (150 mg/kg) or saline were implanted sc in C57BL/6 mice and the drug was delivered as a continuous infusion over 1B4 weeks. The time course of morphological features, collagen content, and pro-inflammatory cytokine expression in the skin and the lungs were analyzed. Pathological examination demonstrated dominant inflammatory infiltrates at week 1 and significant fibrosis at week 4. Decreased microvessel density and increased myofibroblast counts were observed in the skin of BLM-treated mice at week 4. In addition, there were obvious increases in dermal infiltration of CD45 þ leukocytes, including F4/80 þ macrophages, Gr-1 þ neutrophils, and CD3 þ T lymphocytes in BLM-treated mice. IL-1b, IL-4, and CXCL2 transcripts were continually upregulated by BLM in the skin and lung tissues. In addition, lungs from BLM-treated mice showed significant inflammatory infiltrates and confluent subpleural fibrosis at week 4. In conclusion, this modified murine model for drug-induced systemic inflammation and fibrosis uses a single procedure and provides reproducible skin and lung lesions, mimicking human systemic sclerosis (SSc) with ILD-like manifestation.
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