Shukti Chakravarti, Ph.D.
Ranjita GowdaNagaraj, Ph.D.
Zhaoxia Li, Ph.D.
Sherri-Gae Scott, Ph.D.
A major focus in our laboratory is extracellular matrix (ECM), and its role in innate immune inflammatory responses at mucosal surfaces. The ECM has a significant role in modulating the local inflammatory milieu, while its breakdown can present immune cells with endogenous danger signals to drive excessive immune responses. However, these events are poorly understood.
Our studies on lumican, one such ECM protein, shows that its expression increases in Crohn’s disease and mouse models of colitis. We found that a segment of the lumican protein interacts with toll-like receptor 4 on neutrophils and macrophages that regulates innate immune response and production of inflammatory cytokines. We developed mice deficient in lumican that show poor recovery from a chemically induced colitis. The function of lumican in inflammation may be a double-edged sword—needed for development of protective innate immunity but unrestricted can cause immune dysregulation and chronic inflammation.
We are currently investigating the molecular nature of lumican interactions with host immune functions and developing mimetic peptides and anti-lumican antibodies that could be ultimately used to modulate inflammation. Treatments using anti-TNF-α or other antibodies that block major components of the immune response may have harmful immunosuppressive effects.
Future treatment strategies based on lumican or other proteins of the ECM could become milder approaches to suppress localized inflammation. Recently, we have started investigating, biglycan another lumican-like ECM protein that is perceived as an endogenous danger signal in chronic inflammatory settings.
Our laboratory has examined differential gene expression patterns in Crohn’s disease and ulcerative colitis to establish signature expression patterns. A subset of these genes will be pursued in the future for elucidating pathogenesis of these two related inflammatory bowel diseases.
- Lawrance IC, Fiocchi C, Chakravarti S. Gene expression profiling identifies distinctive disease signatures for ulcerative colitis and Crohn's disease. Hum Molec Genet. 2001; 10:445-456.
- Lawrance IC, Wu F, Leite AZA, Willis J,West GA, Fiocchi C, Chakravarti S. A murine model of chronic inflammation-induced intestinal fibrosis down regulated by antisense NF-B. Gastroenterology. 2003; 125:1750-1761.
- Wu F, Dassopoulos T, Cope L, Brant SR, Harris M, Maitra M, Bayless TM, Parmigiani G, Chakravarti S. Genome-wide gene expression differences between Crohn’s and ulcerative colitis from endoscopic pinch biopsies: insights into distinctive pathogenesis. Inflamm Bowel Diseases, 2007; 13:807-821. PMID: 17262812.
- Wu F, Chakravarti S. Differential Expression of Inflammatory and Fibrogenic Genes and Their Regulation by NF-κB Inhibition in a Mouse Model of Chronic Colitis. J Immunol. 2007; 179:6988-7000. PMID: 17982090
- Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, Brant SR, Chakravarti S, Kwon JH. MicroRNAs are Differentially Expressed and Alter Expression of Macrophage Inflammatory Peptide-2alpha. Gastroenterology. 2008 Nov; 135:1624-1635. PMID: 18835392.
- Lee S, Bowrin K, Hamad AR, Chakravarti S. Extracellular matrix lumican deposited on the surface of neutrophils promotes migration by binding to 2 integrin. J Biol Chem. 2009 284:23662-9. PMID: 19531489 PMCID: 2749141.
- Lohr, K, Sardana, H, Lee, S, Wu, F, Huso, DL, Hamad, AR, Chakravarti, S. Extracellular matrix protein lumican regulates inflammation in a mouse model of colitis. Inflamm Bowel Diseases, 2011 Apr 11. doi: 10.1002/ibd.21713. [Epub ahead of print]. PMID: 21484968; PubMed Central PMCID: 3135758.
- Shao H, Lee S, Gae-Scott S, Nakata C, Chen S, Hamad AR, Chakravarti S. Extracellular matrix lumican promotes bacterial phagocytosis and Lum-/- mice show increased Pseudomonas aeruginosa lung infection severity. J Biol Chem. 2012 Aug 3. [Epub ahead of print] PubMed PMID: 22865855 PMCID: 3476255.