Protease; Neutrophils; Lung; Inflammation; Serpins; Apoptosis
Benarafa Charaf, Simon Hans-Uwe (2017), Role of granule proteases in the life and death of neutrophils., in Biochemical and biophysical research communications
, 482, 473-481.
Ataca Dalya, Caikovski Marian, Piersigilli Alessandra, Moulin Alexandre, Benarafa Charaf, Earp Sarah E, Guri Yakir, Kostic Corinne, Arsenivic Yvan, Soininen Raija, Apte Suneel S, Brisken Cathrin (2016), Adamts18 deletion results in distinct developmental defects and provides a model for congenital disorders of lens, lung, and female reproductive tract development., in Biology open
, 5, 1585-1594.
Georgiev Hristo, Ravens Inga, Benarafa Charaf, Förster Reinhold, Bernhardt Günter (2016), Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets., in Nature communications
, 7, 13116-13116.
Giese Madleen, Turiello Nadine, Molenda Nicole, Palesch David, Meid Annika, Schroeder Roman, Basilico Paola, Benarafa Charaf, Halatsch Marc-Eric, Zimecki Michal, Westhoff Mike-Andrew, Wirtz Christian Rainer, Burster Timo (2016), Exogenous cathepsin G upregulates cell surface MHC class I molecules on immune and glioblastoma cells., in Oncotarget
, 7, 74602-74611.
Basilico Paola, Cremona Tiziana Patrizia, Oevermann Anna, Piersigilli Alessandra, Benarafa Charaf (2016), Increased Myeloid Cell Production and Lung Bacterial Clearance in Mice Exposed to Cigarette Smoke., in American journal of respiratory cell and molecular biology
, 54, 424-435.
Burgener Sabrina S, Baumann Mathias, Basilico Paola, Remold-O&apos, Donnell Eileen, Touw Ivo P, Benarafa Charaf (2016), Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1., in Biological Chemistry
, 397, 897-905.
Stoeckle Christina, Geering Barbara, Yousefi Shida, Rozman Sasa, Andina Nicola, Benarafa Charaf, Simon Hans-Uwe (2016), RhoH is a negative regulator of eosinophilopoiesis., in Cell death and differentiation
, 23, 1961-1972.
Modregger Peter, Cremona Tiziana Patrizia, Benarafa Charaf, Schittny Johannes C, Olivo Alessandro, Endrizzi Marco (2016), Small angle x-ray scattering with edge-illumination., in Scientific reports
, 6, 30940-30940.
Dai Chen, Basilico Paola, Cremona Tiziana Patrizia, Collins Paul, Moser Bernhard, Benarafa Charaf, Wolf Marlene (2015), CXCL14 displays antimicrobial activity against respiratory tract bacteria and contributes to clearance of Streptococcus pneumoniae pulmonary infection., in The Journal of Immunology
, 194, 5980-5989.
Benarafa Charaf, Wolf Marlene (2015), CXCL14: the Swiss army knife chemokine., in Oncotarget
, 6, 34065-34066.
Kruger Philipp, Saffarzadeh Mona, Weber Alexander N R, Rieber Nikolaus, Radsak Markus, von Bernuth Horst, Benarafa Charaf, Roos Dirk, Skokowa Julia, Hartl Dominik (2015), Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury., in PLoS pathogens
, 11, 1004651-1004651.
Benarafa Charaf (2015), Regulation of Neutrophil Serine Proteases by Intracellular Serpins, in Geiger Margarethe (ed.), Springer, Switzerland, 329-329.
Rožman S, Yousefi S, Oberson K, Kaufmann T, Benarafa Charaf, Simon H U (2015), The generation of neutrophils in the bone marrow is controlled by autophagy., in Cell death and differentiation
, 22, 445-456.
Benarafa Charaf (2015), Tumor-induced inflammation alters neutrophil phenotype and disease progression., in Breast cancer research : BCR
, 17, 135-135.
Geering Barbara, Stoeckle Christina, Rozman Sasa, Oberson Kevin, Benarafa Charaf, Simon Hans-Uwe (2014), DAPK2 positively regulates motility of neutrophils and eosinophils in response to intermediary chemoattractants., in Journal of leukocyte biology
, 95, 293-303.
Inflammatory responses are vital to preserve host integrity and survival following infection with pathogens. Genetic and environmental factors, however, contribute to modify, enhance or sustain these responses leading inflammatory diseases. Excessive acute amplification can lead to severe disease and lethality such as in acute respiratory distress syndrome and septic shock. Chronic inflammation is associated with sustained release of cytokines and enzymes leading to altered antimicrobial responses, reduced organ function and tissue destruction such as in cystic fibrosis (CF), asthma or chronic obstructive pulmonary disease (COPD) and emphysema. Serine proteases carried in neutrophil and mast cell granules are indiscriminate in their activity and have been shown to contribute to both protective and destructive inflammatory functions. These proteases directly kill pathogens and inactivate toxins but they also induce discrete proteolysis of host proteins with often detrimental consequences. Chronic release of these enzymes in the extracellular milieu, like in CF lung disease, COPD and arthritis, is thought to drive sustained tissue injury and inflammation. At these inflammatory sites, neutrophil death contributes to a large extent to excess protease release and fuels a cycle of that leads to increased neutrophil recruitment and tissue damage. Many studies have focused on neutrophil elastase, its targets and its regulation by plasma and secreted protease inhibitors such as a1-antitrypsin. We propose to investigate the role of the little studied, but increasingly recognized, family of intracellular (clade B) serpins in cellular homeostasis and inflammation.We have previously established that serpinB1, a potent intracellular inhibitor of neutrophil granule proteases (elastase, cathepsin G and proteinase-3), is required to prevent early neutrophil death both at inflammatory sites as well as in the bone marrow. Mice lacking serpinB1 have a severely reduced reserve of mature neutrophils in the bone marrow; they fail to clear Pseudomonas lung infection and have increased morbidity in influenza A virus infection. In these models, lack of serpinB1 is also associated with increased and sustained production of pro-inflammatory cytokines. We have recently identified that the cytoprotective role of serpinB1 depends on the inhibition of cathepsin G in a cell-intrinsic manner. Cathepsin G, but not neutrophil elastase, induced neutrophil death upon granule membrane permeabilization. In the first aim of this proposal, we will define the molecular and cellular signals that trigger the intracellular release of cathepsin G from granules leading to cell death in neutrophils in steady state and in inflammation. We will also investigate the function of serpinB1 and related serpins in mast cell homeostasis and granule-mediated death. In the second aim, we will investigate molecular mechanisms by which serpinB1 regulates neutrophil proteases in mouse models of inflammation. The proposed studies will generate novel findings on the fundamental cytoprotective functions of intracellular serpins and identify the relative importance of different granule proteases and serpins in amplifying and sustaining inflammation. These studies will be highly relevant for better targeting detrimental feedback loops involved in cell death and inflammation in infectious and non-infectious pathologies.