Li Lab

Inflammation, Innate Immunity and Infections:
From Molecular Basis to Translational Research

We primarily focus on understanding the molecular signaling mechanisms by which inflammation, innate immunity and mucosal defense is induced and regulated in the pathogenesis of infectious and inflammatory diseases and further developing novel therapeutic agents for treating these diseases. Multidisciplinary approaches have been undertaken in our laboratory. Those approaches include molecular genetics, cell biology, biochemistry, molecular biology, immunology, pharmacology, functional genomics and proteomics as well as knockout mouse. Currently, we are focusing on the following research areas:

Regulation of Inflammation in Infectious and
Inflammatory Diseases

Inflammation is a hallmark of many serious human diseases including infectious diseases e.g. pneumonia and otitis media (OM), chronic obstructive pulmonary diseases (COPD), asthma, arthritis, heart failure and atherosclerosis as well as cancer. It is the complex biological response of the body to harmful stimuli, such as infectious pathogens, irritants and stress. Appropriate inflammation is a protective host defense response to remove the injurious stimuli as well as initiate tissue healing and repair process. However, overactive inflammation is detrimental to the host, leading to inflammatory diseases. Thus, inflammation must be tightly regulated.

Inducible Negative Feedback Regulation of Inflammation

In contrast to the positive regulation, inducible negative feedback regulation of NF-κB, a key regulator of inflammatory genes, plays a critical role in preventing overactive inflammation. We recently found that CYLD, a novel deubiquitinating (DUB) enzyme that was originally identified as a tumor suppressor, acts as a key negative regulator for NF-κB-dependent inflammation by bacteria and cytokines in vitro and in vivo in an inducible negative feedback manner. We also found that CYLD negatively regulates IKK- and p38 MAPK-mediated NF-κB activation by directly deubiquitinating TRAF6/7. In addition, our data demonstrated that CYLD also acts as a negative regulator for NFAT-dependent inflammatory response likely via a TRAF-independent mechanism. Moreover, CYLD itself is also markedly induced by a variety of inflammatory stimuli including bacteria. Our studies thus provide novel insights into the tight regulation of inflammation and innate defense response and may lead to the identification of novel therapeutic targets for treating infectious and inflammatory diseases. Our future studies will focus on identifying the novel molecular targets of CYLD and the underlying signaling mechanisms involved in inflammatory and infectious diseases including bacterial and viral infections, e.g. nontypeable Haemophilus influenzae (NTHi), Streptococcus pneumoniae (S. pneumoniae) and influenza, COPD, asthma, arthritis, cardiovascular disorders as well as cancers. We will also investigate the signaling mechanisms by which CYLD is induced and regulated by infectious agents and inflammatory stimuli.

Synergistic Regulation of Inflammation


In view of the current studies on regulation of NF-κB-dependent inflammation, most of them have focused on investigating how NF-κB is activated by a single inducer at a time. However, under in vivo conditions, multiple inducers including both pathogenic inducers and physiological fators are present simultaneously. Those in vivo conditions include polymicrobial infections (e.g. mixed infections of bacteria and virus), bacterial pathogen and the cytokines and pathogenic inducers and growth factors. A key issue that has yet to be addressed is whether multiple inducers activate NF-κB-dependent inflammation in a synergistic manner. To date we show that gram-negative bacterium NTHi and gram-positive bacterium S. pneumoniae or TNF-α synergistically induce NF-κB activation via NF-κB translocation-dependent and -independent pathways. Recently, we also found that growth factor TGF-β, traditionally thought as an immune/inflammation suppressor, induces p65 acetylation to synergistically enhance bacteria-induced NF-κB activation and the resultant inflammation. We currently focus on identifying the ligands, e.g. bacterial virulence factors, and their surface receptors (Toll-like vs non-Toll like receptors) as well as their downstream signaling networks underlying the synergistic regulation of NF-κB-dependent inflammation in the pathogenesis of infectious and inflammatory diseases using multidisciplinary approaches including animal models.

Regulation of Toll-like Receptor in Innate Immunity

The recognition of invading microbes followed by the induction of effective innate immune response is crucial for host survival. Human surface epithelial cells are situated at host-environment boundaries, and thus act as the first line of host defense against invading microbes. They recognize the microbial ligands via Toll-like receptors (TLRs) expressed on the surface of epithelial cells. As the immune system needs to constantly strive a balance between activation and inhibition to avoid detrimental and inappropriate inflammatory responses, TLR signaling must be tightly regulated. Our laboratory demonstrated for the first time that TLR2 is expressed at relatively low level in upper respiratory tract under physiological condition but is markedly up-regulated during bacterial infections. Surprisingly, glucocorticoids (GCs), well known potent anti-inflammatory agents, synergistically enhance bacteria-induced TLR2 up-regulation via MKP-1-dependent negative cross-talk with p38 MAPK. Our data suggest that GCs not only suppress host immune and inflammatory responses but may also enhance host defense response possibly by enhancing the expression of host defense receptor TLR, thereby acting as modulators in orchestrating and optimizing immune functions, including host defense during bacterial infections. These studies may bring new insights into the role of bacteria and glucocorticoids in regulating host defense and immune response and lead to novel therapeutic strategies for modulating innate immune and inflammatory responses. We currently focus on investigating how TLR signaling is negatively regulated, e.g. by deubiquitinase CYLD. We are particularly interested in understanding the inducible negative regulation of TLR signaling during bacterial and viral infections.

Regulation of Host Survival in S. pneumoniae and Influenza Infections

Streptococcus pneumoniae (S.p.) is a major cause of morbidity and mortality worldwide. It is a major cause of community-acquired pneumonia (CAP) and also considered as a significant cause of a secondary infection associated with influenza virus infections. Despite the widespread use of antibiotics, the mortality rate from severe S.p. pneumonia remains highest during the first 48 hr of hospitalization and remains unchanged especially in elderly or immune-weakened patients when compared to the pre-antibiotic era. Acute respiratory failure is a hallmark of severe pneumococcal pneumonia. Pneumolysin (PLY), a cytolytic toxin produced by virtually all clinical isolates of S.p., is a key virulence factor for acute lung injury (ALI) in early stage of severe pneumococcal pneumonia. However, little is known about the molecular mechanism by which PLY-induced ALI is induced and regulated. We recently showed that deubiquitinase CYLD deficiency protected mice from PLY-induced ALI and lethality. CYLD was highly induced by PLY, and it inhibited MKK3-p38 MAPK-dependent expression of plasminogen activator inhibitor-1 (PAI-1) in lung, thereby potentiating ALI and mortality. Thus, CYLD is detrimental for host survival, thereby unveiling a novel mechanism underlying the high early mortality of pneumococcal pneumonia. Of particular interest is the identification of protective role of PAI-1 at the early stage of ALI. Future studies will focus on investigating the molecular targets and the underlying signaling mechanisms by which CYLD regulates PLY-induced ALI. These studies will provide novel insights into the molecular mechanisms underlying ALI and death during early stage of severe pneumococcal pneumonia and lead to development of novel therapeutic agent for treating severe pneumococcal infections and reducing death rate in flu.

Regulation of Mucus Overproduction and Innate Mucosal Defense in Bacterial Infections

Mucus overproduction, a hallmark of upper respiratory tract infections including otitis media and COPD, is a primary innate mucosal defensive response for mammalian airways. Mucin, the major protein component of mucus, protect and lubricate the epithelial surface and trap particles, including bacteria and viruses, for mucociliary clearance. In infections, excessive production of mucin occurs, overwhelming the normal mucociliary clearance mechanisms. As mucus levels increase, they contribute significantly to airway obstruction in airway infections and conductive hearing loss in middle ear infections. The molecular signaling mechanisms underlying overproduction of mucin are largely unknown. To date we have found that gram-negative bacterium NTHi up-regulates mucin MUC5AC via a TLR2-depndent p38 MAPK pathway, whereas gram-positive bacterium induces mucin MUC5AC via a TLR4-IKK-depnedent ERK signaling pathway. Interestingly activation of TGF-β-Smad signaling pathway plays distinct roles in differentially regulating induction of mucin MUC5AC and MUC2 genes. We currently focus on the molecular characterization of the novel bacterial virulence factors, the host receptor and its downstream positive and negative signaling pathways as well as the transcription factors and co-activators involved in mucin up-regulation. Moreover we will also explore the functional mimicry of host activities by NTHi because preliminary evidences have suggested that NTHi may manipulate the host signaling pathways possibly using some molecules similarly to host growth factors.

Development of Novel Therapeutic Agents for Inflammatory Diseases

Inflammatory disorders including COPD, otitis media, asthma, atherosclerosis, rheumatoid arthritis, psoriasis and infectious diseases are a substantial burden in social and economic terms with the total cost estimated at $180B annually in the US alone. Despite the importance of these diseases, there have been relatively few innovative breakthroughs into their treatment or cure, despite intensive global research.

Systemic and topically delivered steroids represent one of the main drugs currently used to treat inflammatory diseases. However, steroids have limitations and safety issues for some uses that limit their utility against chronic forms of inflammatory disease. Among the potential adverse effects of steroids are: inhibition of natural hormones, liver damage, suppression of the immune response, effect on cholesterol, aggressive behavior, acne, baldness, kidney impairment, stunted growth and cardiovascular issues. Thus, currently there is an urgent need for developing safe and effective anti-inflammatory agents without significant adverse effects.

Taking advantage of drug repositioning strategy, we have recently demonstrated for the first time that VKI, a well-known natural product, acts as a potent anti-inflammatory agents for inhibiting inflammation in a number of animal models including chronic obstructive pulmonary diseases, otitis media and cardiovascular inflammatory diseases. VKI was originally discovered nearly 30 years ago and has been approved for other clinical applications. Its already approved excellent safety and toxicity profile will significantly reduce clinical trial risk and time as well as the cost for drug development. Thus VKI appears to be a highly promising anti-inflammatory drug candidate that will have a much greater chance to be approved for clinical use.

 

Portrait of Jian-Dong Li, Ph. D.


Jian-Dong Li M.D., Ph.D.
Marie C. & Joseph C. Wilson
Professor of
Microbiology & Immunology

GEBS Cluster Affiliation: IMV


Contact Information:

University of Rochester
School of Medicine
and Dentistry
601 Elmwood Ave, Box 672
Rochester, New York 14642

Phone: (585) 275-7195
Fax: (585) 473-9573

E-mail Dr. Li