Great progress has been made over the past decade in elucidating pathophysiologic mechanisms in airways inflammatory diseases. Considerable controversy remains however, relating to the specific role of chemokines and their receptors in orchestrating the pathology. During the last funding cycle of this grant, we focused on two beta chemokine receptors, CCR1 and CCR3, examining their role, through the use of mice with genetic deletions, in several well-characterized models of lung disease. We additionally characterized eosinophil lineage ablated mice (?dblGATA) in both acute and chronic models of allergic airway inflammation. Our data support CCR3 ligation as the dominant mechanism for eosinophil recruitment, at baseline as well as in response to injury or infection. Using the ?dblGATA mice, we demonstrated that allergic airway hyperresponsiveness occurs in the absence of eosinophils, but that these cells may control features of airway remodeling.
In Specific Aim 1 of this renewal application, we propose experiments to determine whether CCR3-/- mice are similarly protected from allergic airway remodeling. In preliminary studies we find a potential role for CCR1 in the pathophysiology of RSV infection, although complexities are revealed by superimposition of an allergic reaction. In our focus on airway hyperresponsiveness and the role of eosinophils, the newly gleaned variability in the role of this cell type appears to derive from subtleties in the mode of administration and nature of the allergen, as well as background mouse genetics. Since mice (and humans) develop airway hyperresponsiveness to RSV in the absence of an adaptive immune reaction, we have opted to investigate this mechanism of airway injury. We hypothesize a significant role for the fractalkine/CX3CR1 axis in RSV lung disease and will define the mechanism by which the RSV G glycoprotein subverts innate immune responses. Successful completion of these studies will provide additional mechanistic understanding of the pathophysiology of RSV induced lung injury as well as preclinical validation for drug development.
Since mice (and humans) develop airway hyperresponsiveness to RSV in the absence of an adaptive immune reaction, we have opted to investigate this mechanism of airway injury. We hypothesize a significant role for the fractalkine/CX3CR1 axis in RSV lung disease and will define the mechanism by which the RSV G glycoprotein subverts innate immune responses. Successful completion of these studies will provide additional mechanistic understanding of the pathophysiology of RSV induced lung injury as well as preclinical validation for drug development.
|Saxena, Amit; Bujak, Marcin; Frunza, Olga et al. (2014) CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans. Cardiovasc Res 103:217-27|
|Wang, Ruobing; Lu, Bao; Gerard, Craig et al. (2013) Disruption of the complement anaphylatoxin receptor C5L2 exacerbates inflammation in allergic contact dermatitis. J Immunol 191:4001-9|
|Bera, Monali M; Lu, Bao; Martin, Thomas R et al. (2011) Th17 cytokines are critical for respiratory syncytial virus-associated airway hyperreponsiveness through regulation by complement C3a and tachykinins. J Immunol 187:4245-55|
|Koon, Hon Wai; Shih, David; Karagiannides, Iordanes et al. (2010) Substance P modulates colitis-associated fibrosis. Am J Pathol 177:2300-9|
|Nakanishi, Yusuke; Lu, Bao; Gerard, Craig et al. (2009) CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462:510-3|
|Takeda, Atsunobu; Baffi, Judit Z; Kleinman, Mark E et al. (2009) CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature 460:225-30|
|Morteau, Olivier; Gerard, Craig; Lu, Bao et al. (2008) An indispensable role for the chemokine receptor CCR10 in IgA antibody-secreting cell accumulation. J Immunol 181:6309-15|
|Kohlmeier, Jacob E; Miller, Shannon C; Smith, Joanna et al. (2008) The chemokine receptor CCR5 plays a key role in the early memory CD8+ T cell response to respiratory virus infections. Immunity 29:101-13|
|Humbles, Alison A; Lloyd, Clare M; McMillan, Sarah J et al. (2004) A critical role for eosinophils in allergic airways remodeling. Science 305:1776-9|
|Gerard, C; Frossard, J L; Bhatia, M et al. (1997) Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. J Clin Invest 100:2022-7|