Eosinophil‐derived IL‐4 is necessary to establish the inflammatory structure in innate inflammation

Pathogen‐induced inflammation comprises pro‐ and anti‐inflammatory processes, which ensure pathogen removal and containment of the proinflammatory activities. Here, we aimed to identify the development of inflammatory microenvironments and their maintenance throughout the course of a toll‐like receptor 2‐mediated paw inflammation. Within 24 h after pathogen‐injection, the immune cells were organized in three zones, which comprised a pathogen‐containing “core‐region”, a bordering proinflammatory (PI)‐region and an outer anti‐inflammatory (AI)‐region. Eosinophils were present in all three inflammatory regions and adapted their cytokine profile according to their localization. Eosinophil depletion reduced IL‐4 levels and increased edema formation as well as mechanical and thermal hypersensitivities during resolution of inflammation. Also, in the absence of eosinophils PI‐ and AI‐regions could not be determined anymore, neutrophil numbers increased, and efferocytosis as well as M2‐macrophage polarization were reduced. IL‐4 administration restored in eosinophil‐depleted mice PI‐ and AI‐regions, normalized neutrophil numbers, efferocytosis, M2‐macrophage polarization as well as resolution of zymosan‐induced hypersensitivity. In conclusion, IL‐4‐expressing eosinophils support the resolution of inflammation by enabling the development of an anti‐inflammatory framework, which encloses proinflammatory regions.