Abstract
In addition to their well characterized role in mediating IgE-dependent allergic diseases, aberrant accumulation and activation of mast cells (MCs) is associated with many non-allergic inflammatory diseases, whereby their activation is likely triggered by non-IgE stimuli (e.g., IL-33). Siglec-8 is an inhibitory receptor expressed on MCs and eosinophils that has been shown to inhibit IgE-mediated MC responses and reduce allergic inflammation upon ligation with a monoclonal antibody (mAb). Herein, we evaluated the effects of an anti-Siglec-8 mAb (anti-S8) in non-allergic disease models of experimental cigarette-smoke-induced chronic obstructive pulmonary disease and bleomycin-induced lung injury in Siglec-8 transgenic mice. Therapeutic treatment with anti-S8 inhibited MC activation and reduced recruitment of immune cells, airway inflammation, and lung fibrosis. Similarly, using a model of MC-dependent, IL-33-induced inflammation, anti-S8 treatment suppressed neutrophil influx, and cytokine production through MC inhibition. Transcriptomic profiling of MCs further demonstrated anti-S8-mediated downregulation of MC signaling pathways induced by IL-33, including TNF signaling via NF-κB. Collectively, these findings demonstrate that ligating Siglec-8 with an antibody reduces non-allergic inflammation and inhibits IgE-independent MC activation, supporting the evaluation of an anti-Siglec-8 mAb as a therapeutic approach in both allergic and non-allergic inflammatory diseases in which MCs play a role.
Highlights
Mast cells (MCs) are tissue-resident cells that have broad roles in regulating acute and chronic tissue inflammation in a variety of allergic, proliferative, and inflammatory diseases
Therapeutic anti-Sialic-acid-binding immunoglobulin-like lectin (Siglec)-8 monoclonal antibody (mAb) treatment reduces chronic inflammation in cigarette smoke (CS)-induced experimental chronic obstructive pulmonary disease (COPD) To evaluate the inhibitory activity of anti-S8 in chronic non-allergic inflammation, we used a model of CS-induced experimental COPD that has previously been shown to be partially MC-dependent and have several hallmark features of human disease.[3,4]
Siglec-8 has emerged as a promising therapeutic target for allergic and inflammatory diseases due to both its selective expression on MCs and eosinophils and its inhibitory activity
Summary
Mast cells (MCs) are tissue-resident cells that have broad roles in regulating acute and chronic tissue inflammation in a variety of allergic, proliferative, and inflammatory diseases. MCs have been associated with allergic inflammation, during which their activation plays a critical role in driving type-2 inflammatory diseases, such as eosinophilic asthma, atopic dermatitis, and eosinophilic gastrointestinal diseases.[1] Activation of MCs by crosslinking the FcεRI via IgE induces rapid degranulation and the release of preformed mediators, such as histamine, tumor necrosis factor (TNF), and proteases, as well as the subsequent release of de novo synthesized lipid mediators, cytokines, and chemokines. In addition to allergic inflammation, MCs have been implicated in non-allergic diseases, such as inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), type-2 low asthma, idiopathic pulmonary fibrosis (IPF), and psoriasis.[2,3,4] In these disease settings, MCs are likely activated by inflammatory mediators, such as cytokines, Toll-like receptor (TLR) ligands, and neuropeptides.[2,5]
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