Enhanced Airway Th2 Response After Allergen Challenge in Mice Deficient in CC Chemokine Receptor-2 (CCR2)

Abstract

To evaluate the role of CCR2 in allergic asthma, mutant mice deficient in CCR2 (CCR2−/−) and intact mice were sensitized with i.p. OVA with alum on days 0 and 7, and challenged by inhalation with nebulization of either OVA or saline. Airway hyperreactivity, measured by the methacholine-provoked increase in enhanced pause, was significantly increased (p < 0.05) in OVA-challenged CCR2−/− mutant mice, compared with comparably challenged CCR2+/+ mice. OVA-challenged CCR2−/− mutants also were also found to have enhanced bronchoalveolar lavage fluid eosinophilia, peribronchiolar cellular cuffing, and Ig subclass switching, with increase in OVA-specific IgG1 and IgE. In addition, RNase protection assay revealed increased whole lung expression of IL-13 in OVA-challenged CCR2−/− mutants. Unexpectedly, serum monocyte chemotactic protein-1 levels were 8-fold higher in CCR2−/− mutants than in CCR2+/+ mice sensitized to OVA, but OVA challenge had no additional effect on circulating monocyte chemotactic protein-1 in either genotype. Ag stimulation of lymphocytes isolated from OVA-sensitized CCR2 mutants revealed a significant increase (p < 0.05) in IL-5 production, which differed from OVA-stimulated lymphocytes from sensitized CCR2+/+ mice. These experiments demonstrate an enhanced response in airway reactivity and in lung inflammation in CCR2−/− mutant mice compared with comparably sensitized and challenged CCR2+/+ mice. These observations suggest that CC chemokines and their receptors are involved in immunomodulation of atopic asthma.

Absence of CCR8 Does Not Impair the Response to Ovalbumin-Induced Allergic Airway Disease

“…Whereas the response of CCR4-deficient mice in an OVA-induced asthma model was similar to that of WT animals (37), studies neutralizing CCL22/macrophage-derived chemokine (38) or CCL17/ thymus and activation-regulated cytokine (39) showed that blocking either of these CCR4-specific ligands attenuated allergic airway disease development. Conflicting results have also been published in studies of mice deficient in CCR2, a ␤-chemokine receptor reported not to be critical for development of OVA-induced pulmonary inflammation (40), or to modulate the corresponding immune response (41), whereas neutralization of the CCR2 ligand CCL2/monocyte chemoattractant protein-1 was reported to diminish the inflammation drastically (42).…”

Impaired Lung Dendritic Cell Activation in CCR2 Knockout Mice

“…However, the induction of the Th2 response is clearly more complex and persistent or enhanced Th2 responses have been reported in CCR2Ϫ/Ϫ mice. 33,41 Hence, Th1 responses may have a net greater sensitivity to CCR2 knockout, which is intriguing in view of our observation that unlike with PPD challenge, CD40 induction was not as impaired in CCR2Ϫ/Ϫ mice challenged with a Th2-eliciting Ag, SEA.…”

IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

“…Monocyte chemotactic protein (MCP) family chemokines are believed to play particularly important roles in these disorders. This is based on the demonstration that MCP-1 is a potent stimulator of mast cell mediator release, T cell chemotaxis, basophil chemotaxis, and tissue fibrosis, which also enhances naive T cell acquisition of a Th2 cell phenotype (19,22). It is also based on the demonstration that MCP-1, acting via its major receptor, CCR2, is the major recruiter of macrophages at sites of allergic tissue inflammation (23) and that MCP-1, MCP-3, and MCP-4 are expressed in a exaggerated fashion in tissues from patients with asthma (20,21,24,25).…”

“…Although in vitro characterizations would suggest that there is impressive redundancy in this system, examinations of a limited number of ligands in vivo have demonstrated that their production is organized in a coordinated manner and that their effector functions can be restricted to different stages of disease development and/or pathology (17,18,39,44). Thus, in vivo, a deficiency of an individual ligand or its receptor can cause striking alterations in tissue phenotype (16,19). An impressive finding in our study is the potent and rapid induction of MCP-1 and other MCP moieties by IL-13 in the murine lung.…”

“…An impressive finding in our study is the potent and rapid induction of MCP-1 and other MCP moieties by IL-13 in the murine lung. Because MCP-1 signals predominantly via CCR2 and MCP-2, -3, and -5 are also key CCR2 ligands (16,19), the roles of MCP signaling and CCR2 were evaluated by characterizing the IL-13 responses in mice with ϩ/ϩ and Ϫ/Ϫ CCR2 loci. Because prior studies demonstrated that MCP-1 has different effects when exogenously administered during the sensitization vs the elicitation/effector phases of type I and type II granulomatous immune responses (45), care was taken to use a system that allowed the effector mechanisms of IL-13 to be selectively analyzed (see below).…”