The chemokine receptor CXCR2 is the only receptor for ELR+ CXC chemokines in the mouse, deletion of which increases of neutrophils and progenitors in the marrow, as well as systemic expression of G-CSF and IL-17A. Our CXCL5-/- mice, which lack one ligand for CXCR2, express an intermediate phenotype, suggesting involvement of CXCL5 in controlling granulopoiesis through CXCR2. Furthermore, these mice are more resistant to severe pneumonia. Our data suggest that IL-17 regulates this phenotype in response to signals from the environment. Based on new preliminary data indicating that ablation of commensal bacteria impairs lung host defense, we hypothesize that commensal bacteria induce IL-17-expressing lymphoid cells in the gut that is attenuated by CXCL5- induced influx of neutrophils. In the absence of full neutrophil availability, IL-17- producing cells initite a systemic process inducing granulopoiesis and increasing lung host defense. Using murine systems, we will address the following Specific Aims: 1. Determine whether granulocytic hyperplasia in CXCR2-/- and CXCL5-/- mice is due to activation of an IL-1/IL-23/IL-17/G-CSF pathway, addressing whether the source of IL-17 is at mucosal sites, and the role of innate lymphoid cells. 2. Determine whether the IL- 17/G-CSF axis mediates the enhanced lung host defense seen in CXCL5-/- mice, focusing on regulation of trafficking of IL-17 cells and neutrophils, and modification of lung host defense genes 3. Determine the importance of commensal bacteria in regulating host defense through IL-17. These studies will address critical unanswered questions in how alterations in gut microbes may alter the lung resistance to bacterial infection, and offer new routes to enhance host resistance or decrease neutrophilic inflammation in the lung.
Regulation of neutrophil production may influence the extent and severity of inflammation. We propose a multi-step hypothesis in which commensal bacteria induce differentiation of IL-17-producing cells through expression of IL-1 and IL-23. IL-17 induces expression of G-CSF, thereby promoting granulopoiesis, and inducing expression of lung anti-microbial genes. Interaction of apoptotic neutrophils with local mucosal phagocytes dampens IL-1 and IL-23 expression, thus exerting feedback control over granulopoiesis. Ablation of commensal bacteria in Cxcl5-/- mice impairs lung pathogen defense. Understanding these interactions will provide new approaches to infectious and inflammatory diseases of the lung.
|Gibbs, Julie; Ince, Louise; Matthews, Laura et al. (2014) An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat Med 20:919-26|
|Deshmukh, Hitesh S; Liu, Yuhong; Menkiti, Ogechukwu R et al. (2014) The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med 20:524-30|