Role of the Type I IL-4 Receptor (Type I IL-4R) and Insulin Receptor Substrate (IRS)-2 in Allergic Lung Inflammation
AdvisorKeegan, Achsah D.
MetadataShow full item record
AbstractTH2 cytokines, IL-4 and IL-13, play critical roles in allergic lung inflammation and drive alternative activation of macrophages (AAM). They signal through the Type I and Type II receptor (R) complexes. Although both cytokines share receptor subunits, they have differential roles in asthma pathogenesis: IL-4 regulates TH2 cell differentiation, while IL-13 regulates airway hyperreactivity and mucus production. IL-4 signaling through the Type I IL-4R predominantly activates Insulin Receptor Substrate (IRS)-2 and induces AAM gene expression in vitro; AAM can enhance allergic inflammation. The contributions of the Type I and Type II receptors in modulating features of airway inflammation in vivo, however, are unclear. We hypothesized that absence of signaling through the Type I IL-4R and IRS-2 would lead to reduced airway inflammation. Since TH2 differentiation plays a pivotal role in asthma, we first developed a mouse model of this disease using in vivo-primed T cells. To test our hypothesis, we adoptively transferred wild-type OVA-primed CD4+ T cells into Rag2-/-, or gamma c (γc)-/- mice, which lack the Type I IL-4R. Surprisingly, we found that γc-/- mice developed increased lung inflammation and eosinophilia upon OVA challenge when compared to Rag2-/- mice. Lung epithelial cells in both mouse strains expressed AAM proteins FIZZ1 and YM1, while macrophages expressed only YM1. However, the number of FIZZ1+ or YM1+ airways was significantly higher in γc-/- mice. In the γc deficient environment, CD4+ T cells produced greater quantities of TH2 cytokines and IFNγ. These results suggest that in absence of the Type I R, the Type II R can mediate allergic responses when WT TH2 effectors are provided. IFNγ can enhance established TH2 responses, explaining the exaggerated asthma phenotype seen in γc-/- mice. Studies in IRS-2-/- mice demonstrated a negative regulatory role for this protein in allergic airway disease. These mice developed enhanced pulmonary inflammation with significantly increased recruitment of eosinophils and macrophages in comparison to WT mice. Additionally, increased AAM gene/protein expression was detected in macrophages lacking IRS-2 in vitro and in vivo. In conclusion, this study delineated the relative contribution of the Type I R versus the Type II R in asthma pathogenesis.
DescriptionUniversity of Maryland in Baltimore. Molecular Microbiology and Immunology. Ph.D. 2011
Keywordalternative activated macrophages
Insulin Receptor Substrate Proteins