Context-dependent roles of resistin-like molecule β in mucosal defense and inflammatory diseases

Resistin-like molecule β (RELMβ) is a cysteine-rich secreted protein predominantly produced by intestinal goblet cells and regulated by microbial colonization, epithelial transcriptional programs, and immune signals. At the intestinal mucosal surface, recombinant murine and human RELMβ permeabilize susceptible bacterial membranes, while genetic studies in mice support its role in maintaining spatial separation between the microbiota and the epithelium. Murine studies further implicate RELMβ in defense against selected gastrointestinal nematodes, epithelial repair, intestinal inflammation, and the microbiota-dependent establishment of oral tolerance. Beyond the intestine, RELMβ has been associated with pulmonary vascular and airway remodeling, metabolic liver disease, atherosclerosis, abdominal aortic aneurysm, and selected cancers. However, the strength of this evidence varies: most causal findings derive from rodent genetic or intervention models, whereas human evidence is based largely on tissue associations and cultured-cell experiments. Mechanistically, RELMβ may act through at least two non-exclusive modes: direct membrane disruption and modulation of host-cell responses, but the relationship between these activities remains unclear. Its physiological oligomeric state, context-specific molecular interaction partners, and cellular source in the circulation and extraintestinal lesions also remain unresolved. This review distinguishes direct RELMβ evidence from inferences based on other RELM-family proteins and proposes a compartment-interaction system framework that considers protein source, route of exposure, molecular assembly, local physicochemical conditions, and available interaction partners as potential determinants of biological outcome. This framework is presented as a testable synthesis for defining experimental priorities and assessing the biological and therapeutic relevance of RELMβ.