CC Chemokine Receptor-2 Is Not Essential for the Development of Antigen-Induced Pulmonary Eosinophilia and Airway Hyperresponsiveness

Abstract

Monocyte chemoattractant proteins-1 and -5 have been implicated as important mediators of allergic pulmonary inflammation in murine models of asthma. The only identified receptor for these two chemokines to date is the CCR2. To study the role of CCR2 in a murine model of Ag-induced asthma, we compared the pathologic and physiological responses of CCR2−/− mice with those of wild-type (WT) littermates following immunization and challenge with OVA. OVA-immunized/OVA-challenged (OVA/OVA) WT and CCR2−/− mice developed significant increases in total cells recovered by bronchoalveolar lavage (BAL) compared with their respective OVA-immunized/PBS-challenged (OVA/PBS) control groups. There were no significant differences in BAL cell counts and differentials (i.e., macrophages, PMNs, lymphocytes, and eosinophils) between OVA/OVA WT and CCR2−/− mice. Serologic evaluation revealed no significant difference in total IgE and OVA-specific IgE between OVA/OVA WT mice and CCR2−/− mice. Lung mRNA expression and BAL cytokine protein levels of IL-4, IL-5, and IFN-γ were also similar in WT and CCR2−/− mice. Finally, OVA/OVA CCR2−/− mice developed increased airway hyper-responsiveness to a degree similar to that in WT mice. We conclude that following repeated airway challenges with Ag in sensitized mice, the development of Th2 responses (elevated IgE, pulmonary eosinophilia, and lung cytokine levels of IL-4 and IL5) and the development of airway hyper-responsiveness are not diminished by a deficiency in CCR2.

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.…”

“…27,31,32 Blocking of CCR2 function in vivo suppresses Th1 development. 11,29,31,33,34 However, in vitro culture failed to show differences in Th1 differentiation between CCR2-deficient and wild-type control T cells. 25 Moreover, in a mouse autoimmune encephalitis model, adoptively transferred myelin oligodendrocyte glycoprotein 35-55-specific T cells lacking expression of CCR2 were able to induce experimental autoimmune encephalitis, whereas CCR2Ϫ/Ϫ recipients of wild-type T cells failed to develop disease.…”

Differential Roles of CC Chemokine Ligand 2/Monocyte Chemotactic Protein-1 and CCR2 in the Development of T1 Immunity

“…A similar discrepancy has been observed for CCL2 and CCR2 in producing eosinophilia during allergic pulmonary inflammation in mice. CCL2 neutralization has been shown to abolish eosinophilia associated with the pulmonary allergic response (7), while CCR2 deletion does not diminish (33) or even increases eosinophilia (19,34). Increased eosinophilia following CCL2 neutralization in C. neoformans infection does not occur despite the fact that lung leukocytes isolated from these mice produce high levels of IL-5 (Fig.…”

Platelet-Activating Factor Receptor Develops Airway Hyperresponsiveness Independently of Airway Inflammation in a Murine Asthma Model

“…Recently, Hogan et al (9) proposed a novel pathway to the development of AHR intimately mediated by CD4 ϩ T cells independently of IL-4 and IL-5, although the details of this pathway remain unknown. The relative contribution of these three cellular pathways to the induction of AHR is likely to be dependent on a number of factors including the strain of mouse, the choice of Ag, and the protocols for Ag sensitization and challenge, which may account for the apparent conflict observed among the mouse asthma models used by different investigators (9,32,39,(53)(54)(55)(56). In the present study, we induced AHR in BALB/c mice with the procedure of Foster and coworkers (9,32,54,57,58) who have provided corroborative evidence of the important role of IgE, eosinophils, Th2 cytokines, and CD4 ϩ T cells.…”