Publications
Wilson C.B., Ray M., Lutz M.A., Sharda D., Xu J., Hankey P.A. The RON receptor tyrosine kinase regulates IFN-gamma production and responses in innate immunity. J Immunol. 2008 Aug 15;181(4):2303-10.
Huang G.N., Huso D.L., Bouyain S., Tu J., McCorkell K.A., May M.J., Zhu Y., Lutz M.A., Collins S., Dehoff M., Kang S., Whartenby K., Powell J., Leahy D., Worley P.F. NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science. 2008 Jan 25; 319(5862): 476-81.
Collins S., Lutz M.A., Zarek P.E., Anders R.A., Kersh G.J., Powell J.D. Opposing regulation of T cell function by Egr-1/NAB2 and Egr-2/Egr-3. Eur J Immunol. 2008 Feb; 38(2): 528-36.
Zheng Y., Collins S., Lutz M.A., Allen A., Kole T., Zarek P., Powell J.D. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol. 2007 Feb; 178(4): 2163-70.
Scheibner K.A., Lutz M.A., Boodoo S., Fenton J.D. and Horton M.R. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol. 2006 Jul; 177(2): 1272-81.
Safford M., Collins S., Lutz M.A.*, Allen A., Huang C.T., Kowalski J., Blackford A., Horton M.R., Drake C., Schwartz R.H. and Powell J.D. Egr-2 and Egr-3 are negative regulators of T cell activation. Nat Immunol. 2005 May; 6(5): 472-80. (* co-first author)
Correll P.H., Morrison A.C. and M.A. Lutz. Receptor tyrosine kinases and the regulation of macrophage activation. J Leuko Biol. 2004 May; 75(5): 731-7.
Lutz M.A., Liu Q-P. and P.H. Correll. Activation of CR3-mediated phagocytosis by MSP requires the RON receptor, tyrosine kinase activity, phosphatidylinositol 3-kinase and protein kinase C zeta . J Leuko Biol. 2003 Jun; 73(6): 802-14. (+ cover figure)
Lutz M.A., (2003) The role of the MSP/RON signaling pathway in CR3 activation and the regulation of inflammation in vitro and in vivo. Ph.D. Thesis. Pennsylvania State University, University Park. 146 p.
Lutz M.A., Gervais F., Berstein A., Hattel A.L. and P.H. Correll. STK receptor tyrosine kinase regulates susceptibility to infection with Listeria monocytogenes. Infect Immun. 2002 Jan; 70(1): 416-8.
Works in Progress
Lutz M.A., and Powell J.D. The roles of Egr 2/3, mTOR and Cbl-b during tolerance induction via CD4+CD25+FoxP3 T regulatory cells. (in preparation)
Abstracts / Presentations
Lutz M.A., Collins S. and Powell J.D. (2006) The roles of Egr-2/3, mTOR and Cbl-b during anergy induction. Keystone Symposia - Lymphocyte Activation and Signaling, Steamboat Springs, CO.
Wilson C.B., Morrison A.C., Lutz M.A. and P.H. Correll. (2004) Activation of the RON receptor tyrosine kinase by MSP induces the phosphorylation of STAT3 and the upregulation of SOCS 1 & 3 in primary peritoneal macrophages. Experimental Biology 2004 (The American Association of Immunologists), Washington D.C.
Lutz M.A., Morrison A.C. and P.H. Correll. (2003) The STK receptor tyrosine kinase is expressed on tissue-resident macrophages and protects tissues from inflammatory damage. 36th annual meeting of the Society for Leukocyte Biology, Philadelphia, PA.
Lutz M.A., Takakura N., Suda T. and P.H. Correll. (2003) The STK receptor tyrosine kinase is expressed on Kupffer cells and protects the liver from inflammatory damage. Keystone Symposia, Taos, NM.
Lutz M.A., Liu Q-P. and P.H. Correll. (2002) Downstream signaling events from the RON receptor tyrosine kinase related to MSP activation of CR3-mediated phagocytosis in primary peritoneal macrophages. Experimental Biology 2002 (The American Association of Immunologists), New Orleans, LA.
Lutz M.A. and P.H. Correll. (2000) Activation of complement-mediated phagocytosis by MSP through the RON receptor. The American Association of Immunologists and the Clinical Immunology Society Joint Annual Meeting, Seattle, WA.
Lutz M.A. and P.H. Correll. (2000) Activation of complement-mediated phagocytosis by MSP through the RON receptor. 28th annual Mid-Atlantic Immunobiology Conference, State College, PA.
The roles of Egr-2/3, mTOR and Cbl-b during anergy induction
Lutz M.A., Collins S. and Powell J.D.
TCR engagement in the absence of proper accessory signals leads to T cell tolerance. Recently we have identified the zinc-finger transcription factors, Egr-2 and Egr-3, as playing a role in promoting the induction of T cell anergy. One of the genes that appear to be regulated by Egr-2 and Egr-3 is the E3 ligase, Cbl-b. Indeed Cbl-b has been shown to be upregulated during anergy induction and mediate its effects in part through inhibition of PLC-gamma phosphorylation. Consequently, Cbl-b deficient T cells and mice are resistant to the induction of tolerance in vitro and in vivo. Overexpression of Egr-2 and Egr-3 was associated with an increase in Cbl-b and inhibition of T cell activation. Conversely, T cells from Egr-3 null mice expressed lower amounts of Cbl-b and were resistant to in vivo peptide-induced tolerance. However, while Cbl-b upregulation can account for the immediate defects seen in anergy, Cbl-b cannot readily explain the long-term hyporesponsiveness. Alternatively, rapamycin, a pharmacological inhibitor of mTOR, has been shown to promote stable T cell anergy under full activation. Therefore, we hypothesize that the effects of Cbl-b are ultimately related to mTOR activity of the cell. To test this hypothesis, we adoptively transferred wild-type or Cbl-b -/- clonotypic T cells into the in vivo model of peptide-induced anergy in the presence or absence of rapamycin. Recipients of Cbl-b -/- T cells were resistant to peptide-induced anergy compared to wild-type controls. However, this resistance to tolerance in the Cbl-b null mice was reversed by the presence of rapamycin. That is mTOR inhibition promoted anergy even in the Cbl-b T cells. These data support the view that mTOR acts downstream of Cbl-b mediated inhibition and is critical in determining T cell activation versus tolerance.
The STK receptor tyrosine kinase is expressed on tissue-resident macrophages and protects tissues from inflammatory damage
Lutz M.A., Morrison A.C. and Correll P.H.
There is a growing body of evidence to suggest that receptor tyrosine kinases (RTKs) regulate macrophage activation and innate immunity. The STK receptor kinase, and the closely related Mer receptor, inhibit NF-kappaB activation by LPS and mice with targeted deletions in both of these receptors are more susceptible to endotoxic shock, associated with increased serum levels of TNF-alpha and nitric oxide. In addition, we and others have shown that MSP, the ligand for the STK receptor, inhibits the expression of inducible nitric oxide synthase (iNOS), IL-12 p40 and Cox-2 in primary peritoneal macrophages activated by IFN-gamma and LPS. Alternatively, MSP induces expression of genes associated with alternative activation including arginase I, IL-1Ra and SR-A. Expression of STK is relatively restricted to long-lived tissue resident macrophages and while its expression is inhibited by IFN-gamma and LPS in a NO-dependent manner, expression of STK is induced on exudate macrophages and can be upregulated in vitro by IL-4, dexamethasone and hypoxia. Here we demonstrate that STK is expressed on Kupffer cells, tissue-resident liver macrophages, and that mice lacking STK exhibit increased liver damage, as measured by serum AST and ALT, in response to acute injury induced by D-gal and LPS. Furthermore, this damage can be partially ameliorated by the administration of the NO inhibitor, aminoguanidine. In addition to its role in the regulation of the innate immune response, we also demonstrate that MSP stimulation of primary peritoneal macrophages in vitro results in the inhibition of Th1 and Th2 differentiation following co-culture with D011.10 CD4+ T cells under strong polarizing conditions. Subsequently, STK-deficient mice exhibit increased inflammation in a contact-sensitivity DTH response. Taken together, these data suggest that the expression of STK on tissue resident macrophages limits classical macrophage activation and CD4+ T cell activation, resulting in the protection of host tissues from inflammatory damage.
The STK receptor tyrosine kinase is expressed on Kupffer cells and protects the liver from inflammatory damage
Lutz M.A., Takakura N., Suda T. and Correll P.H.
Stem cell-derived tyrosine kinase (STK) is expressed on a subset of tissue-resident macrophages. Previous studies have shown that macrophage stimulating protein (MSP), the ligand for STK, suppresses the production of nitric oxide by primary murine peritoneal macrophages in response to IFN-gamma and LPS stimulation, through inhibition of inducible nitric oxide synthase (iNOS) expression. Mice with a targeted deletion in exon 1 of the gene encoding STK exhibit increased sensitivity to endotoxic shock, associated with elevated serum levels of NO. Therefore, we proposed a model in which the expression of STK on tissue-resident macrophages limits the ability of those cells to produce NO, thus protecting host tissues from damage during an immune response. In order to test this hypothesis, we examined the expression and function of STK in Kupffer cells, tissue-resident liver macrophages. Kupffer cells are the most abundant mononuclear phagocytes in the body, and these cells play a central role in the uptake and clearance of endotoxin from the portal circulation. As such, these macrophages are primed for phagocytosis and express high levels of CR3, but their ability to produce NO is limited compared with other macrophages population. Here we show that Kupffer cells express STK and that LPS administration results in increased NOS activity in the livers of STK-deficient mice compared to wild-type littermate controls. In order to quantitate the effects of the absence of STK on liver damage in response to endotoxin, we injected STK-deficient mice and their littermate controls with variable doses of LPS in the presence of D-galactosamine, and measured serum levels of the liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In these studies, STK-deficient animals exhibited elevated levels of AST and ALT in the serum in response to low doses of LPS, and the NO inhibitor, aminoguanidine, was able to ameliorate this response. Histological analysis revealed acute multifocal hepatocellular necrosis in the livers of STK-deficient animals. These data support a role for STK in protecting the liver from NO-mediated inflammatory damage in response to endotoxin.
Downstream signaling events from the RON receptor tyrosine kinase related to MSP activation of CR3-mediated phagocytosis in primary peritoneal macrophages
Lutz M.A., Liu Q-P., and Correll P.H.
Macrophage stimulating protein (MSP) has multiple effects on resident populations of macrophages. In addition to its ability to induce shape change, promote chemotaxis, and suppress nitric oxide production in response to LPS stimulation, MSP has been shown to promote complement-mediated phagocytosis through activation of the alphaMbeta2 integrin (CR3). MSP induced complement-mediated phagocytosis occurs through the RON receptor tyrosine kinase (RTK) and increasing evidence shows that RTK’s and integrins are able to cooperate to transduce signaling events. Co-immunoprecipitation studies suggest a ligand-independent interaction between the RON receptor and CR3. Additionally, we show that MSP activation of the RON receptor results in tyrosine phosphorylation, PI 3-kinase dependent AKT activation and PKC zeta localization in primary peritoneal macrophages and we show how these signals influence CR3-mediated phagocytosis. Finally, we demonstrate that both C3bi-coated erythrocytes and MSP share the ability to inhibit nitric oxide by LPS/IFN-gamma stimulated macrophages. Based on these studies, we propose a model in which the RON receptor and CR3 cooperate to regulate phagocytosis and inflammation in macrophages.
Activation of complement-mediated phagocytosis by MSP through the RON receptor
Lutz M.A. and Correll P.H.
Macrophage stimulating protein (MSP) has multiple effects on resident populations of macrophages. MSP has been shown to induce shape change, promote chemotaxis, and suppress nitric oxide production in response to IFN-gamma. In addition, MSP promotes complement-mediated phagocytosis, but not Fc receptor-mediated phagocytosis. This effect of MSP is mediated through the receptor tyrosine kinase, RON, as evidenced by the inability of RON -/- peritoneal macrophages to augment phagocytosis of complement coated sheep erythrocytes in response to MSP. By using various inhibitors, the ability of the MSP/RON pathway to activate complement -mediated phagocytosis was compared with PMA. Activation of calcium-dependent PKC isoforms by PMA is responsible for complement-mediated phagocytosis through serine/threonine phosphorylation of complement receptors. However, based on studies using different PKC inhibitors, the ability of MSP/RON to activate complement-mediated phagocytosis appears to depend on the activation of the calcium-independent PKC isoform zeta. The PI 3-kinase inhibitors, wortmannin and LY294002 were able to inhibit MSP/RON complement-mediated phagocytosis in a dose dependent manner. MSP/RON and PMA complement-mediated phagocytosis also requires the formation of contractile microfilaments, which can be inhibited by cytochalasin B. Herbimycin A, a protein kinase inhibitor was able to inhibit MSP/RON complement-mediated phagocytosis, but not PMA induced phagocytosis. The above results suggest that the ability of MSP/RON to activate complement-mediated phagocytosis requires tyrosine phosphorylation, PI 3-kinase and PKC zeta, and actin assembly.