Dataset Information

Interleukin-1? Mediates Ozone-Induced Myeloid Differentiation Factor-88-Dependent Epithelial Tissue Injury and Inflammation.

ABSTRACT: Air pollution associated with ozone exposure represents a major inducer of respiratory disease in man. In mice, a single ozone exposure causes lung injury with disruption of the respiratory barrier and inflammation. We investigated the role of interleukin-1 (IL-1)-associated cytokines upon a single ozone exposure (1?ppm for 1?h) using IL-1?-, IL-1?-, and IL-18-deficient mice or an anti-IL-1? neutralizing antibody underlying the rapid epithelial cell death. Here, we demonstrate the release of the alarmin IL-1? after ozone exposure and that the acute respiratory barrier injury and inflammation and airway hyperreactivity are IL-1?-dependent. IL-1? signaling via IL-1R1 depends on the adaptor protein myeloid differentiation factor-88 (MyD88). Importantly, epithelial cell signaling is critical, since deletion of MyD88 in lung type I alveolar epithelial cells reduced ozone-induced inflammation. In addition, intratracheal injection of recombinant rmIL-1? in MyD88acid mice led to reduction of inflammation in comparison with wild type mice treated with rmIL-1?. Therefore, a major part of inflammation is mediated by IL-1? signaling in epithelial cells. In conclusion, the alarmin IL-1? released upon ozone-induced tissue damage and inflammation is mediated by MyD88 signaling in epithelial cells. Therefore, IL-1? may represent a therapeutic target to attenuate ozone-induced lung inflammation and hyperreactivity.

SUBMITTER: Michaudel C

PROVIDER: S-EPMC5950844 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Interleukin-1α Mediates Ozone-Induced Myeloid Differentiation Factor-88-Dependent Epithelial Tissue Injury and Inflammation.

Michaudel Chloé C Maillet Isabelle I Fauconnier Louis L Quesniaux Valérie V Chung Kian Fan KF Wiegman Coen C Peter Daniel D Ryffel Bernhard B

Frontiers in immunology 20180507

Air pollution associated with ozone exposure represents a major inducer of respiratory disease in man. In mice, a single ozone exposure causes lung injury with disruption of the respiratory barrier and inflammation. We investigated the role of interleukin-1 (IL-1)-associated cytokines upon a single ozone exposure (1 ppm for 1 h) using IL-1α-, IL-1β-, and IL-18-deficient mice or an anti-IL-1α neutralizing antibody underlying the rapid epithelial cell death. Here, we demonstrate the release of the ...[more]

PMID: 29867931

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Project description:Synthetic hydrogels, such as poly(ethylene glycol) (PEG), are promising for a range of in vivo applications. However, like all non-biological biomaterials, synthetic hydrogels including PEG elicit a foreign body response (FBR). The FBR is thought to be initiated by adsorbed protein that is recognized by and subsequently activates inflammatory cells, notably macrophages, and culminates with fibrotic encapsulation. However, the molecular mechanisms that drive the FBR are not well understood. Toll-like receptors (TLRs) are key receptors that recognize pathogens, but also recognize altered host proteins that display damage-associated molecular patterns (DAMPs). Thus TLRs may play a role in the FBR. Here, we investigated myeloid differentiation primary response gene 88 (MyD88), a signaling adaptor protein that mediates inflammatory cytokine production induced by most TLRs. An in vitro model was used consisting of macrophages cultured on the surface of synthetic hydrogels, specifically PEG, with pre-adsorbed serum proteins. Our in vitro findings demonstrate that MyD88-dependent signaling is the predominant inflammatory pathway in macrophage activation to synthetic hydrogels. When stimulated with TLR agonists to mimic additional DAMPs present in vivo, MyD88-dependent signaling was also the predominant pathway in macrophage activation. An in vivo model of PEG hydrogels implanted subcutaneously in wild-type and MyD88-/- mice also demonstrated that MyD88 is the key contributor to the recruitment of inflammatory cells and formation of the fibrous capsule surrounding the implanted hydrogel. Taken together, findings from this study identify MyD88-mediated inflammation as being a critical pathway involved not only in the inflammatory response, but in formation of the fibrous capsule to PEG hydrogels. STATEMENT OF SIGNIFICANCE: Synthetic hydrogels are promising for in vivo applications but, like all non-biological biomaterials, synthetic hydrogels elicit a foreign body response (FBR). The molecular mechanisms that drive the FBR are not well understood. This work identifies the myeloid differentiation primary response gene 88 (MyD88) as a central mediator to macrophage activation in response to a poly(ethylene glycol) hydrogel with pre-adsorbed proteins in vitro. Moreover, MyD88 was also central to the recruitment of inflammatory cells, which included neutrophils, monocytes, and macrophages, to implanted PEG hydrogels and to fibrous encapsulation. These findings demonstrate that MyD88-mediated inflammation is responsible in part for the formation of the fibrous capsule of the FBR.

Dataset Information

Interleukin-1? Mediates Ozone-Induced Myeloid Differentiation Factor-88-Dependent Epithelial Tissue Injury and Inflammation.

Publications

Interleukin-1α Mediates Ozone-Induced Myeloid Differentiation Factor-88-Dependent Epithelial Tissue Injury and Inflammation.

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