Th17 cells provide protective immunity against certain, but not all, bacterial infections through the recruitment of neutrophils. Receptor interacting protein 2 (Rip2), the adapter molecule used by the intracellular peptidoglycan sensors Nod1 and Nod2, plays an important role in directing innate immune responses against various bacteria (1). However, Th17 cells produce the cytokines IL-17A, IL-17F, and IL-22 that have been linked to chronic inflammatory diseases of skin (i.e., psoriasis), lung (i.e., asthma and chronic obstructive pulmonary disease), and gut (i.e., Crohn's disease). We study the important human pathogen, Chlamydia pneumoniae (CP) that has been associated with chronic conditions such as allergic asthma, chronic lung diseases, exacerbation of chronic obstructive pulmonary disease, and as well as the progression of other chronic inflammatory diseases such as atherosclerosis and lung cancer in smokers. We previously found that Rip2 in alveolar macrophages played a critical role in controlling CP infection in mice, yet surviving Rip2-/- mice developed a profound chronic lung inflammation including enhanced lung fibrosis (2). Unexpectedly, we found that Rip2-deficient T cells were intrinsically skewed towards Th17 and IL-17A production, revealing a novel role for Rip2 in regulating Th17 differentiation. Our preliminary studies show that under conditions of pathogenic (IL-1?-driven) Th17 differentiation, Rip2-/- T cells exhibit enhanced Th17 differentiation and increased expression of retinoic acid-related orphan receptor alpha (ROR?), an important transcription factor that contributes to Th17 skewing. Our data also support the hypothesis that the chronic inflammation seen in Rip2-/- mice after CP infection is a result of the intrinsic Th17 skewing defect in Rip2-/- T cells, independent of IL-17 effects on bacterial killing. Given the increasing identification of NOD/Rip2 polymorphisms associated with various IL-17-driven chronic inflammatory diseases in humans, including severe asthma and Crohn's disease, we will seek to determine the functional implications of this novel Rip2-Th17 regulatory axis in T cells. Based upon these key novel findings, we propose the following studies focused around the central hypothesis that Rip2 deficiency in T cells intrinsically enhances Th17 differentiation, thereby inducing chronic inflammation during CP infection, and that deletion of NODs/RIP2 increases Th17 skewing through enhanced ROR? activity. To test these hypotheses, we propose the following three Specific Aims:
Aim 1. To determine the role of IL- 17 signaling during CP infection and chronic lung inflammation and fibrosis.
Aim 2. To determine the role of the Rip2/IL-17 axis in CP infection-induced chronic lung inflammation/lung fibrosis and the role of human Rip2 SNPs in Th17 skewing in Th17-driven disease.
Aim 3. To investigate the molecular mechanisms by which Rip2 regulates Th17 differentiation. At the conclusion of these studies, we expect to have delineated this novel Th17 regulatory pathway in T cells and have identified key targets for therapeutically mitigating Th17-mediated chronic inflammatory diseases.

Public Health Relevance

The objective of this application is to investigate the role Th17 T-cells in the development of chronic lung inflammation and fibrosis using a well-established model of Chlamydia pneumoniae pulmonary infection as a model system. The overall goal is to investigate a novel mechanism by which Rip2 suppresses Th17 differentiation in mice and humans and play a role in many chronic inflammatory diseases in human.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Davidson, Wendy F
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Cedars-Sinai Medical Center
Los Angeles
United States
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Tumurkhuu, Gantsetseg; Dagvadorj, Jargalsaikhan; Porritt, Rebecca A et al. (2018) Chlamydia pneumoniae Hijacks a Host Autoregulatory IL-1? Loop to Drive Foam Cell Formation and Accelerate Atherosclerosis. Cell Metab 28:432-448.e4
Chen, Shuang; Shimada, Kenichi; Crother, Timothy R et al. (2018) Chlamydia and Lipids Engage a Common Signaling Pathway That Promotes Atherogenesis. J Am Coll Cardiol 71:1553-1570
Shimada, Kenichi; Porritt, Rebecca A; Markman, Janet L et al. (2018) T-Cell-Intrinsic Receptor Interacting Protein 2 Regulates Pathogenic T Helper 17 Cell Differentiation. Immunity 49:873-885.e7
Noval Rivas, Magali; Crother, Timothy R; Arditi, Moshe (2016) The microbiome in asthma. Curr Opin Pediatr 28:764-771