CCL7 and CXCL10 Orchestrate Oxidative Stress-Induced Neutrophilic Lung Inflammation

Abstract

Oxidative stress from ozone (O3) exposure augments airway neutrophil recruitment and chemokine production. We and others have shown that severe and sudden asthma is associated with airway neutrophilia, and that O3 oxidative stress is likely to augment neutrophilic airway inflammation in severe asthma. However, very little is known about chemokines that orchestrate oxidative stress-induced neutrophilic airway inflammation in vivo. To identify these chemokines, three groups of BALB/c mice were exposed to sham air, 0.2 ppm O3, or 0.8 ppm O3 for 6 h. Compared with sham air, 0.8 ppm O3, but not 0.2 ppm O3, induced pronounced neutrophilic airway inflammation that peaked at 18 h postexposure. The 0.8 ppm O3 up-regulated lung mRNA of CXCL1,2,3 (mouse growth-related oncogene-α and macrophage-inflammatory protein-2), CXCL10 (IFN-γ-inducible protein-10), CCL3 (macrophage-inflammatory protein-1α), CCL7 (monocyte chemoattractant protein-3), and CCL11 (eotaxin) at 0 h postexposure, and expression of CXCL10, CCL3, and CCL7 mRNA was sustained 18 h postexposure. O3 increased lung protein levels of CXCL10, CCL7, and CCR3 (CCL7R). The airway epithelium was identified as a source of CCL7. The role of up-regulated chemokines was determined by administering control IgG or IgG Abs against six murine chemokines before O3 exposure. As expected, anti-mouse growth-related oncogene-α inhibited neutrophil recruitment. Surprisingly, Abs to CCL7 and CXCL10 also decreased neutrophil recruitment by 63 and 72%, respectively. These findings indicate that CCL7 and CXCL10, two chemokines not previously reported to orchestrate neutrophilic inflammation, play a critical role in mediating oxidative stress-induced neutrophilic airway inflammation. These observations may have relevance in induction of neutrophilia in severe asthma.

CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection

“…It has previously been shown that CCL7 also binds to CCR3 on eosinophils to induce chemotaxis and activation (19). Airway epithelial cells and macrophages produce CCL7, which may orchestrate cell recruitment in the context of oxidative stress (20,21). Induction of CCL7 during viral infections has been observed in asthmatic patients (22) and in models of RV infection dissecting the role of CCL2 (23).…”

ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation

“…In previous studies, we (58) and others (60) have shown that oxidative stress in the lungs can increase expression of inflammatory chemokines and induce recruitment of neutrophils. Our present data indicate that pollen NADPH oxidases induce 4-HNE and GSSG in airwaylining fluid and that these contribute to IL-8 production, p38 MAPK activation, and neutrophil recruitment.…”

“…Cellular infiltration into the airway lumen was assessed by an analysis of BAL fluid at 72 hours after challenge, as we have described previously (5,6,10,58).…”

Role of CCL7 in Type I Hypersensitivity Reactions in Murine Experimental Allergic Conjunctivitis

“…CCL7 was shown to activate monocytes, basophils, and eosinophils, and it acts as a chemoattractant for a variety of cells, including those associated with allergy (e.g., monocytes, memory T lymphocytes, eosinophils, basophils, dendritic cells, and NK cells) (28)(29)(30). CCL7 was further linked to the pathology of a variety of allergic and inflammatory disease, including asthma (31,32), airway inflammation in response to oxidative stress (33), aspirin allergy (34), and allergic rhinitis (35). CCL7 production is increased in mice that develop allergic lung inflammation in response to Arizona sand dust (36) and in mice challenged with respiratory allergens (37).…”

“…CCL7 production is increased in mice that develop allergic lung inflammation in response to Arizona sand dust (36) and in mice challenged with respiratory allergens (37). CCL7 recruits neutrophils as part of airway inflammation in response to oxidative stress (33), and pretreatment of mice with anti-CCL7 reduces the inflammation and eosinophilia associated with respiratory allergy (37).…”