Research Focus

Immune cell signaling in inflammation: Mechanism and its application

Microbial infection, tissue injury or surgical trauma leads to the release of chemical mediators by immune cells that in turn give rise to the initiation of inflammation in the host. Loss of a balanced immune response regulation leads to several inflammatory disorders such as arthritis, inflammatory bowel disease, and septic shock. Sustained inflammatory cytokine production by macrophages contributes to prolonged cytokine elevation in vivo. Although this sustained cytokine response is believed to play an essential role in maintaining the inflammatory states that accompany or induce many inflammatory diseases, its regulatory mechanism is not fully identified. My research programs mainly focus on the investigation of regulatory mechanism of initiation, sustention, and resolution of inflammation in immune responses, and application to the development of novel therapeutic strategies.

I. Mechanism of 4-1BBL-mediated sustained inflammation: target of anti-inflammation

A member of TNF superfamily, 4-1BBL plays an essential role in controlling sustained TNF production in the response of macrophages to endotoxin. Production of TNF by LPS was not different in wildtype or 4-1BBL-deficient macrophages during the first 3-4 hours after stimulation (early phase), but TNF production was not sustained in 4-1BBL-deficient macrophages as it was in the wildtype macrophages (late phase).The goal is to study the activation and regulatory mechanisms of the 4-1BBL-mediated signaling pathway in sustained inflammatory immune responses. The identification of the sequential signaling pathways in initial and sustained TNF production in LPS-treated macrophages has unveiled how the TNF production is regulated; however, there are still gaps in our knowledge of how the 4-1BBL-mediated signaling pathway controls TNF production. Preliminary results show that 4-1BBL is essential for the resistance to LPS-induced septic shock, and inhibition of 4-1BBL-mediated signaling results in the reduction of TNF production in LPS-stimulated macrophages. Thus this observation may lead to the development of new strategy to treat inflammatory diseases by targeting 4-1BBL.

II. Role of p38α MAPK pathway in the regulation of inflammatory responses: development of therapeutic strategies

         p38α MAPK pathway was discovered and cloned in studying intracellular signaling pathway of inflammatory and stress responses. Evidence to support the importance of the p38α pathway in inflammation comes from several sources, and it is believed that activation of the p38α pathway plays an essential role in inflammation in immune responses. Despite it has been studied vigorously to explain the signaling mechanism, the detailed mechanisms of p38α pathway in innate and adaptive immune cells are unclear. We are currently studying the role of p38a in microbial infection and the inflammatory disorders using mouse models to identify the detailed mechanism of p38a-mediated inflammation for the future therapeutic application.

III. Exploration of the cellular events that control the initiation, sustention and resolution of inflammatory responses.

               Despite intensive and vigorous attempts to resolve the regulation of cell signaling pathways in inflammation and infection, many questions are unanswered. Many signaling molecules that participate in the regulation of inflammation were identified; other important molecules are still being discovered. One of the major concerns in this area is how to control the unnecessary and unbeneficial inflammatory responses that damage the host. It is necessary to discover other molecules that might play a critical role in the regulation of inflammation, which can be the target of anti-inflammation. One attempt is investigating the role of miRNA in the regulation of inflammatory responses by the innate immune cells. The miRNAs play an important role in the development and regulation of immunity. Novel inflammatory signaling pathways that are regulated by miRNA will be identified. 

Selected References

Kang, Y. J., M. Lu, and K.-L. Guan. The TSC1 and TSC2 tumor suppressors are required for proper ER stress response and protect cells from ER stress-induced apoptosis. Cell Death Differ. 2011. 18;133–144.

Kang, Y.J.*, M. Otsuka*, A. van den Berg, L. Hong, Z. Huang, X. Wu, D.-W. Zhang, B. A. Vallance, P. S. Tobias, and J. Han. Epithelial p38α Controls Immune Cell Recruitment in the Colonic Mucosa. Plos Pathogen. 2010. 6(6): e1000934.doi:10.1371/journal.ppat.1000934. *, equal contribution.

Otsuka, M., Y. J. Kang, J. Ren, H. Jiang, Y. Wang, M. Omata, and J. Han. Distinct Effects of p38α Deletion in Myeloid Lineage and Gut Epithelia in Mouse Models of Inflammatory Bowel Disease. Gastroenterology. 2010. 138:1237-1239.

Kang, Y.J.*, J. Chen*, M. Otsuka, J. Mols, S. Ren, Y. Wang and J. Han. Macrophage deletion of p38a partially impairs LPS-induced cellular activation. J Immunol. 2008, 180: 5075-5082. *, equal contribution.

Kang, Y.J., S.O. Kim, S. Shimada, M. Otsuka, A. Seit-Nebi, T. Watts, B.S. Kwon, and J. Han. Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages. Nat. Immunol. 2007. 8: 601-609.

Kang, Y.J.*, B. Kusler, M. Otsuka, M. Hughes, N. Suzuki, S. Suzuki, W.-C. Yeh, S. Akira, J. Han and P.P. Jones*. Calcineurin negatively regulates Toll-like receptor-mediated activation pathways. J. Immunol. 2007. 179: 4598-4607. *Corresponding authors.

Kang, Y.J., A. Seit-Nebi, R.J. Davis and J. Han. Multiple activation mechanisms of p38α MAP kinase. J Biol Chem. 2006. 281:26225-26234.