Kristi L. Williams, PhD
Assistant Research Professor
Departments of Cell Biology and Immunology

Regulation of pulmonary inflammation by the CATERPILLER/NLR gene family

Toll-like receptors (TLRs) have rapidly emerged as a dominant route by which the mammalian innate immune system recognizes microbial pathogens. Pathways downstream of the TLRs require activation of a number of downstream intracellular signaling proteins including MyD88, IRAK-1, and TRAF6. Activation of TLRs present on the surface of innate immune cells leads to the expression of inflammatory mediators including cytokines and chemokines which regulate the adaptive immune response. Recent evidence suggests that activation of TLR2 induces a T helper type 2 (TH2) immune response and promotes experimental asthma. Consequently, the TLR pathway serves as a bridge between innate and adaptive immunity. Analysis of TLR signaling pathways is important for understanding the regulation of immune responses of many disease states including allergy and asthma as many TLRs share similar signaling pathways leading to induction of inflammatory mediators.

Dr. Williams was involved in the identification of a family of orthologs of the plant disease R genes which were called the CATERPILLER/NLR gene family during her postdoctoral fellowship with Dr. Jenny Ting. Approximately 30 CATERPILLER genes are present in the mouse genome, while about 20 are found in the human genome. Protein products of the CATERPILLER/NLR family contain a nucleotide binding domain (NBD) and leucine rich repeats (LRR), and are proposed to have important microbial resistance functions in mammals as well as in plants. This family includes the class II transactivator (CIITA), NOD1, NOD2, cryopyrin, and the gene which Dr. Williams cloned and called Monarch-1. A strong clue that CATERPILLER proteins are likely critical regulators of the immune response, inflammation, and host response to pathogens is the genetic linkage of several CATERPILLER gene products in susceptibility to immunologic disorders. For example, mutations in CIITA are linked to a severe immunodeficiency called Bare lymphocyte syndrome, and mutations in NOD2 are associated with a subpopulation of patients with Crohn's disease and Blau's syndrome. Mutations in the cryopyrin gene are associated with a variety of clinical autoinflammatory syndromes. Mutations in NOD1 have been implicated in inflammatory bowel disease, eczema, and more recently, in asthma. These studies suggest that other CATERPILLER gene family members may be important players both in the maintenance of normal immune responses and the onset of inflammatory disorders.

Dr. Williams was responsible for the identification and cloning of a CATERPILLER family member which she called Monarch-1 and others called PYPAF7. Monarch-1 is primarily expressed by cells of the innate immune system, namely granulocytes, monocytes, and eosinophils but not in lymphocytes or non-hematopoietic tissues. Monarch-1 expression is reduced in primary bronchial lavage samples from humans susceptible to allergic inflammation. In primary monocytes, Monarch-1 expression is dramatically reduced by TLR agonists as well as infection with Mycobacterium tuberculosis. Recent experiments have revealed that Monarch-1 is a negative regulator of TLR induced NF-kB activation, which is critical in regulating the immune response. NF-kB activation by the TLRs, as well as activity of the downstream signaling proteins MyD88, IRAK-1, and TRAF6 are greatly attenuated by Monarch-1. Thus, Monarch-1 is a negative regulator of TLR-induced responses by interfering with TLR signaling proteins. Further research revealed that Monarch-1 was found in a protein complex with the downstream TLR signaling proteins IRAK-1 and NIK suggesting that Monarch-1 may directly regulate proteins within the TLR pathway. Taken together, these data suggest that Monarch-1 is likely to be involved in regulating a plethora of innate immune responses in many disease states including pulmonary infection and asthma.

Current research in the laboratory includes investigating the regulation of Monarch-1 expression as another tool to determine the function of Monarch-1. To understand the role of Monarch-1 in vivo, we will assess the role of Monarch-1 in mouse models of pulmonary inflammation using Monarch-1 null mice. Dr. Williams is also collaborating with physicians to determine the potential role of using Monarch-1 expression as a clinical disease marker of infection. Further characterization of Monarch-1 expression in individuals with a history of asthma as well as pulmonary infections is an important step in the development of therapeutics to target the function of Monarch-1.