{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:46:30Z","timestamp":1792525590370,"version":"4.5.0"},"reference-count":94,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Interleukin-5 (IL-5) is central to eosinophil differentiation, survival, and activation. Subsequent studies confirmed IL-5 receptor expression and mapped downstream signaling, showing that IL-5 promotes not only survival but also trafficking and effector functions, including adhesion, degranulation, reactive oxygen species generation, mediator release (cytokines and cysteinyl leukotrienes), and extracellular trap formation. However, the roles of eosinophils vary across diseases and tissue compartments. Multi-omics analyses of blood and tissue eosinophils across transcriptomic, proteomic, and lipid-metabolic layers reveal disease- and site-specific molecular states. These data support two opposing classes of modulators that shape IL-5\u2013driven programs: pro-inflammatory signals (IL-4\/IL-13, IL-33, NOD2-mediated innate signaling, and IFN-\u03b3) that drive inflammatory eosinophil changes and can cooperate in some settings, and counter-regulatory signals (IFN-\u03b1 and all-trans retinoic acid [ATRA]) that restrain these changes. Such modulation may influence tissue retention, effector functions, and broader eosinophil activities, including antiviral and homeostatic roles. Clinical studies of anti-IL-5 and\/or anti-IL-5R\u03b1 biologics in severe eosinophilic asthma, chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndromes, and other eosinophilic diseases have improved outcomes, underscoring that disease activity often depends on IL-5-driven eosinophil activation despite disease-specific IL-5\u2013independent signals. In this review, we summarize IL-5 biology from mechanisms to therapy and discuss how integrated multi-omics signatures and clinical biomarkers may guide patient stratification, therapy selection, and treatment sequencing toward precision medicine for eosinophilic respiratory and systemic diseases.\u2003<\/jats:p>","DOI":"10.3389\/fimmu.2026.1836661","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T04:20:59Z","timestamp":1776140459000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Pro-inflammatory and counter-regulatory modulators of interleukin-5\u2013driven eosinophil programs: a framework for precision medicine in eosinophilic diseases"],"prefix":"10.3389","volume":"17","author":[{"given":"Hisashi","family":"Sasaki","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical 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Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00576-2021","article-title":"Type 2 inflammation in asthma and other airway diseases","volume":"8","author":"Maspero","year":"2022","journal-title":"ERJ Open Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-01048-y","article-title":"Spatial adaptation of eosinophils and their emerging roles in homeostasis, infection and disease","volume":"24","author":"Arnold","year":"2024","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/all.16303","article-title":"Interleukin-5 as a pleiotropic cytokine orchestrating airway type 2 inflammation: Effects on and beyond 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