Final Report Summary - RELM-A IN THE LUNG (Expression and function or Resistin-like molecule alpha in asthma pathogenesis and fibrosis.)
During the past four years we have focused on the following two aims:
Aim 1: To define the expression of Relm-α in allergic inflammatory lung inflammation and fibrosis.
Achievement #1:
1. Using two independent experimental asthma models models, we have shown that Relm-α is highly upregulated in the allergic lung. We were further able to demonstrate that:
2. Under baseline conditions, Relm-α is expressed only in airway epithelial cells.
3. Following allergen (OVA and Aspergillus fumigatus), IL-13 or IL-4 challenges to the lung, Relm-α is upregulated in alveolar macrophages an airway epithelial cells. Despite our previous findings indicating that gastrointestinal eosinophils express Relm-α, following allergen challenge, Relm-α is not expressed in eosinophils.
4. We have demonstrated that the upregulation in Relm-α expression following allergen challenge is partially dependent on the type 2 IL-4 receptor following OVA challenge but entirely IL-13Rα1-dependent following Aspergillus fumigatus challenge.
The results of this study were published in:
Munitz A, Cole ET, Karo-Atar D, Finkelan FD, Rothenberg ME. Resistin-like molecule alpha regulates IL-13-induced chemokine production but not allergen-induced airway responses. Am J Respir Cell Mol Biol; 2012;46:703-13.
Impact factor: 4.148 Rank: 5/48 (Respiratory)
Achievement #2:
We have identified that the expression of Relm-alpha in the lungs during fibrosis is regulated by an inhibitory receptor termed paired immunoglobulin-like receptor B. PIR-B was upregulated in subsets of lung myeloid cells following bleomycin administration. Bleomycin-treated Pirb-/- mice displayed increased lung histopathology and increased expression of the IL-4-associated profibrogenic markers Relm-α, MMP-12, TIMP-1 and osteopontin, which were localized to alveolar macrophages. Increased profibrogenic mediator expression in Pirb-/- mice was not due to increased IL-4/IL-13 levels, suggesting that PIR-B negatively regulates IL-4-induced macrophage activation. Indeed, IL-4 treated Pirb-/- mice displayed increased Relm-α expression and Relm-α+ macrophage levels.. Furthermore, IL-4-activated Pirb-/- macrophages displayed increased Relm-α and MMP-12 induction. Finally, LILRB3/ILT-5, the human PIR-B ortholog was expressed and upregulated in lung biopsies from IPF patients
A complete summary of these results can be found in:
PIR-B regulates pulmonary fibrosis by suppressing profibrogenic properties of alveoalar macrophages. Karo-Atar D, Moshkovits I, Eickelberg O, Königshoff M, Munitz A. Am J Resp Cell Mol Biol; 2013;48:456-64
Impact factor: 5.125 Rank: 5/48 (Respiratory)
Achievement #3:
In addition, and given the interesting role of PIR-B to regulate macrophage response, we have expanded our knowledge regarding the roles of PIR-B in eosinophils, which are key effector cells in the allergic response. Our studies revealed a critical role for PIR-B and PIR-A in eosinophil development. PIR-B suppressed PIR-A-induced eosinophil apoptosis, thereby counterbalancing survival and growth signals selectively driven by IL-5. PIR expression was regulated by IL-5 and increased during distinct eosinophil maturation stages. Eosinophils maintained a dominant expression of PIR-B over PIR-A under homeostatic conditions. Thus, despite abundant MHC-I ligand availability, which may trigger PIR-A-induced apoptosis, eosinophil development was intact due to inhibitory signals driven by PIR-B. Furthermore, we demonstrate that PIR-A bound the adaptor protein Grb2 and that apoptotic eosinophils displayed increased Erk activation and Bim expression. These data open a new paradigm in our understanding of the intrinsic molecular pathways regulating IL-5-induced eosinophilia and highlight self-recognition via PIRs as a key molecular checkpoint in eosinophil expansion.
A complete summary of this study can be found in:
Ben Baruch-Morgenstern N, Shik D, Moshkovits I, Itan M, Karo-Atar D, Bouffi C, Fulkerson P, Rashkovan D, Jung S, Rothenberg ME, Munitz A. Paired immunoglobulin-like receptor A is an intrinsic, self-limiting suppressor of IL-5-induced eosinophil development. Nature Immunol. 2014;15:36-44. DOI:10.1038/ni2757
Impact factor: 26.19 Rank: 3/135 (Immunology)
Aim 2. To define the function of Relm-α in allergic inflammatory lung responses and lung fibrosis.
Achievement #3:
Given the induction of Relm-α following lung allergen challenge and following IL-13 treatment to the lung, we were set to determine the roles of Relm-α in IL-13 and allergen-induced responses. For this, Relm-α gene targeted mice were challenged with IL-13, IL-4 or allergen and inflammatory lung responses were assessed. To this end we were able to demonstrate that:
1. Relm-α regulates IL-13–induced lung chemokine production. In particular, Relm-α–deficient mice display elevated concentrations of CCL24, CCL2, and CCL11 and decreased concentrations of CCL17 and CCL22. Notably, IL-13–challenged Retnlb deficient mice displayed significantly more CCL2 and less CCL22 than IL-13–challenged Retnla deficient mice.
2. Relm-α does not have a marked role in the overall Th2 response in the lung, as assessed by the production of lung Th2 cytokine, chemokine, cellular recruitment, and mucus production
A complete summary of these results can be found in:
Rothenberg ME, Cole ET, Shik D, Mingler MM, Munitz A. IL-13 receptor 1 differentially regulates aeroallergen induced lung responses. J Immunol; 2011; 187:4873-80.
Impact factor: 5.73 Rank: 24/135 (Immunology)
Achievement #4:
Given the induction of Relm-α following lung allergen challenge and following IL-13 treatment to the lung, we were set to determine the roles of IL-13 receptor alpha 1 in idiopathic pulmonary fibrosis. To this end we identified that human idiopathic pulmonary fibrosis patients display altered expression of IL-13 receptor chains, a phenomenon that is mimicked in the lungs of bleomycin-treated mice. Integrating the data obtained from multiple in vivo models with global microarray analyses revealed that IL-13Rα1 has a central role in lung epithelial cell homeostasis. Thus, in the absence of IL-13Rα1, epithelial cells diaplsy altered expression of RElm-α. Interestingly, in response to bleomycin-induced injury, Il13ra1-/- mice displayed augmented pathology. Importantly, excessive fibrosis in Il13ra1-/- mice was not due to increased responsiveness to IL-17 or to suppressive activity of IL-13. We further demonstrated that IL-13Rα1 was required for absolutely all the transcriptional changes induced by IL-13 in the lungs and that additional IL-13R chains or IL-4 signaling does not mediate the increased pathology observed in bleomycin-treated Il13ra1-/- mice. Collectively, these data suggest that lack of homeostatic signaling by IL-13Rα1 may predispose towards fibrotic lung disease.
A complete summary of results that were obtained from this study are now under revision in:
Karo-Atar D, Bordowitz A, Wand O, Pasmanik-Chor M2 Fernandez IE, Itan M, Frenkel R, Herbert DR, Eickelberg O, Munitz A. A protective role for IL-13 receptor α 1 in bleomycin-induced pulmonary fibrosis. Mucosal Immunology, 2014; In Revision
Impact factor: 7, Rank: 15/135 (Immunology)
Aim 1: To define the expression of Relm-α in allergic inflammatory lung inflammation and fibrosis.
Achievement #1:
1. Using two independent experimental asthma models models, we have shown that Relm-α is highly upregulated in the allergic lung. We were further able to demonstrate that:
2. Under baseline conditions, Relm-α is expressed only in airway epithelial cells.
3. Following allergen (OVA and Aspergillus fumigatus), IL-13 or IL-4 challenges to the lung, Relm-α is upregulated in alveolar macrophages an airway epithelial cells. Despite our previous findings indicating that gastrointestinal eosinophils express Relm-α, following allergen challenge, Relm-α is not expressed in eosinophils.
4. We have demonstrated that the upregulation in Relm-α expression following allergen challenge is partially dependent on the type 2 IL-4 receptor following OVA challenge but entirely IL-13Rα1-dependent following Aspergillus fumigatus challenge.
The results of this study were published in:
Munitz A, Cole ET, Karo-Atar D, Finkelan FD, Rothenberg ME. Resistin-like molecule alpha regulates IL-13-induced chemokine production but not allergen-induced airway responses. Am J Respir Cell Mol Biol; 2012;46:703-13.
Impact factor: 4.148 Rank: 5/48 (Respiratory)
Achievement #2:
We have identified that the expression of Relm-alpha in the lungs during fibrosis is regulated by an inhibitory receptor termed paired immunoglobulin-like receptor B. PIR-B was upregulated in subsets of lung myeloid cells following bleomycin administration. Bleomycin-treated Pirb-/- mice displayed increased lung histopathology and increased expression of the IL-4-associated profibrogenic markers Relm-α, MMP-12, TIMP-1 and osteopontin, which were localized to alveolar macrophages. Increased profibrogenic mediator expression in Pirb-/- mice was not due to increased IL-4/IL-13 levels, suggesting that PIR-B negatively regulates IL-4-induced macrophage activation. Indeed, IL-4 treated Pirb-/- mice displayed increased Relm-α expression and Relm-α+ macrophage levels.. Furthermore, IL-4-activated Pirb-/- macrophages displayed increased Relm-α and MMP-12 induction. Finally, LILRB3/ILT-5, the human PIR-B ortholog was expressed and upregulated in lung biopsies from IPF patients
A complete summary of these results can be found in:
PIR-B regulates pulmonary fibrosis by suppressing profibrogenic properties of alveoalar macrophages. Karo-Atar D, Moshkovits I, Eickelberg O, Königshoff M, Munitz A. Am J Resp Cell Mol Biol; 2013;48:456-64
Impact factor: 5.125 Rank: 5/48 (Respiratory)
Achievement #3:
In addition, and given the interesting role of PIR-B to regulate macrophage response, we have expanded our knowledge regarding the roles of PIR-B in eosinophils, which are key effector cells in the allergic response. Our studies revealed a critical role for PIR-B and PIR-A in eosinophil development. PIR-B suppressed PIR-A-induced eosinophil apoptosis, thereby counterbalancing survival and growth signals selectively driven by IL-5. PIR expression was regulated by IL-5 and increased during distinct eosinophil maturation stages. Eosinophils maintained a dominant expression of PIR-B over PIR-A under homeostatic conditions. Thus, despite abundant MHC-I ligand availability, which may trigger PIR-A-induced apoptosis, eosinophil development was intact due to inhibitory signals driven by PIR-B. Furthermore, we demonstrate that PIR-A bound the adaptor protein Grb2 and that apoptotic eosinophils displayed increased Erk activation and Bim expression. These data open a new paradigm in our understanding of the intrinsic molecular pathways regulating IL-5-induced eosinophilia and highlight self-recognition via PIRs as a key molecular checkpoint in eosinophil expansion.
A complete summary of this study can be found in:
Ben Baruch-Morgenstern N, Shik D, Moshkovits I, Itan M, Karo-Atar D, Bouffi C, Fulkerson P, Rashkovan D, Jung S, Rothenberg ME, Munitz A. Paired immunoglobulin-like receptor A is an intrinsic, self-limiting suppressor of IL-5-induced eosinophil development. Nature Immunol. 2014;15:36-44. DOI:10.1038/ni2757
Impact factor: 26.19 Rank: 3/135 (Immunology)
Aim 2. To define the function of Relm-α in allergic inflammatory lung responses and lung fibrosis.
Achievement #3:
Given the induction of Relm-α following lung allergen challenge and following IL-13 treatment to the lung, we were set to determine the roles of Relm-α in IL-13 and allergen-induced responses. For this, Relm-α gene targeted mice were challenged with IL-13, IL-4 or allergen and inflammatory lung responses were assessed. To this end we were able to demonstrate that:
1. Relm-α regulates IL-13–induced lung chemokine production. In particular, Relm-α–deficient mice display elevated concentrations of CCL24, CCL2, and CCL11 and decreased concentrations of CCL17 and CCL22. Notably, IL-13–challenged Retnlb deficient mice displayed significantly more CCL2 and less CCL22 than IL-13–challenged Retnla deficient mice.
2. Relm-α does not have a marked role in the overall Th2 response in the lung, as assessed by the production of lung Th2 cytokine, chemokine, cellular recruitment, and mucus production
A complete summary of these results can be found in:
Rothenberg ME, Cole ET, Shik D, Mingler MM, Munitz A. IL-13 receptor 1 differentially regulates aeroallergen induced lung responses. J Immunol; 2011; 187:4873-80.
Impact factor: 5.73 Rank: 24/135 (Immunology)
Achievement #4:
Given the induction of Relm-α following lung allergen challenge and following IL-13 treatment to the lung, we were set to determine the roles of IL-13 receptor alpha 1 in idiopathic pulmonary fibrosis. To this end we identified that human idiopathic pulmonary fibrosis patients display altered expression of IL-13 receptor chains, a phenomenon that is mimicked in the lungs of bleomycin-treated mice. Integrating the data obtained from multiple in vivo models with global microarray analyses revealed that IL-13Rα1 has a central role in lung epithelial cell homeostasis. Thus, in the absence of IL-13Rα1, epithelial cells diaplsy altered expression of RElm-α. Interestingly, in response to bleomycin-induced injury, Il13ra1-/- mice displayed augmented pathology. Importantly, excessive fibrosis in Il13ra1-/- mice was not due to increased responsiveness to IL-17 or to suppressive activity of IL-13. We further demonstrated that IL-13Rα1 was required for absolutely all the transcriptional changes induced by IL-13 in the lungs and that additional IL-13R chains or IL-4 signaling does not mediate the increased pathology observed in bleomycin-treated Il13ra1-/- mice. Collectively, these data suggest that lack of homeostatic signaling by IL-13Rα1 may predispose towards fibrotic lung disease.
A complete summary of results that were obtained from this study are now under revision in:
Karo-Atar D, Bordowitz A, Wand O, Pasmanik-Chor M2 Fernandez IE, Itan M, Frenkel R, Herbert DR, Eickelberg O, Munitz A. A protective role for IL-13 receptor α 1 in bleomycin-induced pulmonary fibrosis. Mucosal Immunology, 2014; In Revision
Impact factor: 7, Rank: 15/135 (Immunology)