Mast cell-derived interleukin-4 mediates activation of dendritic cell during toll-like receptor 2-mediated inflammation.

Introduction: During an innate inflammation, immune cells form distinct pro- and anti-inflammatory regions around pathogen-containing core-regions. Mast cells are localized in an anti-inflammatory microenvironment during the resolution of an innate inflammation, suggesting antiinflammatory roles of these cells. Methods: High-content imaging was used to investigated mast cell-dependent changes in the regional distribution of immune cells during an inflammation, induced by the toll-like receptor (TLR)-2 agonist zymosan. Results: The distance between the zymosan-containing core-region and the anti-inflammatory region, described by M2-like macrophages, increased in mast cell-deficient mice. Absence of mast cells abolished dendritic cell (DC) activation, as determined by CD86-expression and localized the DCs in greater distance to zymosan particles. The CD86- DCs had a higher expression of the pro-inflammatory interleukins (IL)-1ß and IL-12/23p40 as compared to activated CD86+ DCs. IL-4 administration restored CD86 expression, cytokine expression profile and localization of the DCs in mast cell-deficient mice. The IL-4 effects were mast cell-specific, since IL-4 reduction by eosinophil depletion did not affect activation of DCs. Discussion: We found that mast cells induce DC activation selectively at the site of inflammation and thereby determine their localization within the inflammation. Overall, mast cells have antiinflammatory functions in this inflammation model and limit the size of the pro-inflammatory region surrounding the zymosan-containing core region.

Meloxicam treatment disrupts the regional structure of innate inflammation sites by targeting the pro-inflammatory effects of prostanoids.

BACKGROUND AND PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed drugs in the world due to their analgesic, antipyretic and anti-inflammatory effects. However, NSAIDs inhibit prostanoid synthesis, interfering with their pro-inflammatory and anti-inflammatory functions and potentially prolonging acute inflammation. EXPERIMENTAL APPROACH: We used high-content immunohistochemistry to define the impact of meloxicam treatment on spatially separated pro-inflammatory and anti-inflammatory processes during innate inflammation in mice induced by zymosan. This allowed us to determine the effect of meloxicam treatment on the organization of pro-inflammatory and anti-inflammatory microenvironments, thereby identifying relevant changes in immune cell localization, recruitment and activation. KEY RESULTS: Meloxicam treatment reduced zymosan-induced thermal hypersensitivity at early time points but delayed its resolution. High-content immunohistochemistry revealed that the pro-inflammatory area was smaller after treatment, diminishing neutrophil recruitment, M1-like macrophage polarization, and especially phagocytosis by neutrophils and macrophages. The polarization of macrophages towards the M2-like anti-inflammatory phenotype was unaffected, and the number of anti-inflammatory eosinophils actually increased. CONCLUSION AND IMPLICATIONS: High-content immunohistochemistry was able to identify relevant meloxicam-mediated effects on inflammatory processes based on alterations in the regional structure of inflammation sites. Meloxicam delayed the clearance of pathogens by inhibiting pro-inflammatory processes, causing prolonged inflammation. Our data suggest that the prescription of NSAIDs as a treatment during an acute pathogen-driven inflammation should be reconsidered in patients with compromised immune systems.

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.