IL‐37 alleviates house dust mite‐induced chronic allergic asthma by targeting TSLP through the NF‐κB and ERK1/2 signaling pathways

Abstract

Interleukin (IL)-37 has been described as a negative regulator of immune responses and is critical for asthma pathogenesis, but the mechanisms behind the protective role of IL-37 against allergic asthma are less well understood. We show here that IL-37 administered intranasally inhibited house dust mite (HDM)-induced chronic airway eosinophilic inflammation, goblet cell hyperplasia, peribronchial collagen deposition and airway hyperresponsiveness (AHR) to methacholine. In contrast to a weakened Th2 response in the lung that was characterized by the downregulation of Th2-associated cytokines and chemokines in IL-37-treated mice, IL-37 has no effect on relevant markers of systemic Th2 immune including serum immunoglobulins expression and in vitro production of Th2-associated cytokines by splenocytes on HDM recall. We demonstrated that the production of thymic stromal lymphopoietin (TSLP) in the lung tissue was associated with IL-37. Importantly, compared with IL-37 alone, TSLP coadministration with IL-37 restored HDM-induced airway inflammation and structural alterations, increased AHR to methacholine and promoted Th2-associated cytokine production. We further found that IL-37 inhibited the induction of TSLP expression by the main antigen of house dust mite, Der p1, by suppressing NF-jB and extracellular signal regulated kinase 1/2 (ERK1/2) activation in human bronchial epithelial (16-HBE) cells in vitro. These data highlight the importance of TSLP in IL-37-mediated protective role in asthma. IL-37 might represent a useful innovative and alternative therapy to control TSLP production in the airway.

IL‐37b alleviates inflammation in the temporomandibular joint cartilage via IL‐1R8 pathway

“…38,39 In addition, some reports showed that IL-37 inhibited inflammation by inhibiting NF-κB activation. 40 Our data revealed that in the chondrocytes, IL-37b downregulated ERK, JNK and p38 MAPK signals and inhibited NF-κB translocation into the nucleus after IL-1β stimulation. In contrast, silencing IL-1R8 led to inflammation upregulation by enhancing these signals.…”

Current Understanding of IL-37 in Human Health and Disease

“…On the one hand, IL-37 alleviates airway inflammation and remodeling in ovalbumin -induced asthma via inhibiting the activation of NF-kB and STAT3 signalings (104). On the other hand, IL-37 not only targets TSLP through NF-kB and ERK1/2 signaling pathways (105), but also may act on tracheobronchial epithelial cells to inhibit fibroblasts and AMSC from producing CCL11, thereby alleviating house dust mite(HDM)-induced asthma (106). Importantly, IL-37b significantly inhibits the production of inflammatory factors in the co-culture of human primary eosinophils and human bronchial epithelial BEAS-2B cells after the stimulation of bacterial TLR-2 ligand peptidoglycan (107).…”

Recent Advances in Progresses and Prospects of IL-37 in Central Nervous System Diseases

“…In vivo experiments in an atopic dermatitis mouse model showed alternative depletion of basophils rescued atopic dermatitis symptoms and significantly lowered the helper T cell 2 (Th2) and eosinophil populations in the ear and spleen [ 24 ]. In other studies, therapeutic effects of IL-37 on allergic diseases, autoimmune diseases, and other immune system diseases have been reported [ 6 , 25 , 26 , 27 , 28 ]. In addition, IL-37 reportedly exerts tumor-inhibiting effects in a variety of cancers, such as breast, cervical, melanoma, and non-small cell lung cancer [ 12 , 29 ]; refer to the relevant review for details.…”