Abstract
The objective of this study was to investigate the relationship between autophagy and allergic inflammation. In vitro allergic inflammation was accompanied by an increased autophagic flux in rat basophilic leukemia (RBL2H3) cells. 3-MA, an inhibitor of autophagic processes, negatively regulated allergic inflammation both in vitro and in vivo. The role of p62, a selective receptor of autophagy, in allergic inflammation was investigated. P62, increased by antigen stimulation, mediated in vitro allergic inflammation, passive cutaneous anaphylaxis (PCA), and passive systemic anaphylaxis (PSA). P62 mediated cellular interactions during allergic inflammation. It also mediated tumorigenic and metastatic potential of cancer cells enhanced by PSA. TargetScan analysis predicted that miR-135-5p was a negative regulator of p62. Luciferase activity assay showed that miR-135-5p directly regulated p62. MiR-135-5p mimic negatively regulated features of allergic inflammation and inhibited tumorigenic and metastatic potential of cancer cells enhanced by PSA. MiR-135-5p mimic also inhibited cellular interactions during allergic inflammation. Extracellular vesicles mediated allergic inflammation both in vitro and in vivo. Extracellular vesicles were also necessary for cellular interactions during allergic inflammation. Transmission electron microscopy showed p62 within extracellular vesicles of antigen-stimulated rat basophilic leukemia cells (RBL2H3). Extracellular vesicles isolated from antigen-stimulated RBL2H3 cells induced activation of macrophages and enhanced invasion and migration potential of B16F1 mouse melanoma cells in a p62-dependent manner. Extracellular vesicles isolated from PSA-activated BALB/C mouse enhanced invasion and migration potential of B16F1 cells, and induced features of allergic inflammation in RBL2H3 cells. Thus, miR-135-5p-p62 axis might serve as a target for developing anti-allergy drugs.
Highlights
Impaired autophagy in myeloid cells has a causal role in eosinophilic inflammation and chronic rhino sinusitis [1]
We present a novel role of miR-135-5p-p62 axis in regulating allergic inflammation in conjunction with autophagic flux, cellular interactions, and allergic inflammationpromoted enhanced tumorigenic and metastatic potential of cancer cells
We showed the presence of p62 within extracellular vesicles and the role of p62 in cellular interactions mediated by extracellular vesicles during allergic inflammation
Summary
Impaired autophagy in myeloid cells has a causal role in eosinophilic inflammation and chronic rhino sinusitis [1]. Autophagy plays a crucial role in degranulation of mast cells [3, 4]. MTOR, an inhibitor of autophagy, mediates metabolic adaptation of antigen presenting cells (APCs) in distinct tissues, influencing immunological characters of allergic inflammation [8]. Inhibition of PI3K/Akt activity and subsequent blockade of mTOR-hypoxia inducible factor (HIF)-1α-vascular endothelial growth factor (VEGF) module can attenuate typical asthmatic attack in a murine model [9]. HDAC3 can interact with FcεRIβ and mediate allergic inflammation by increasing expression of monocyte chemo attractant protein 1 (MCP1) [11]. Down-regulation of HDAC3 abrogates the ability of HDAC inhibitor valproic acid (VPA) to modulate AKT phosphorylation, suppress tumor cell growth, and induce autophagy [12]. Autophagy might play a role in allergic inflammation
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