Prostaglandin E2 and IL-23 plus IL-1β differentially regulate the Th1/Th17 immune response of human CD161(+) CD4(+) memory T cells

Prostaglandin E2 (PGE2), interleukin (IL)-23, and IL-1beta (β) propagate inflammatory bowel disease (IBD) by enhancing the development and function of IL-17 producing CD4(+) T helper (Th17) cells. CD4(+) T cells that express the C-type lectin-like receptor CD161 have been proposed to be the physiologic pool of circulating Th17 cells implicated in IBD. We sought to understand how PGE2, alone and in combination with IL-23 and IL-1β, modulate human peripheral CD161(+) CD4(+) memory T cells. We found that CD161(+) cells comprise a significant proportion of human peripheral CD4(+) memory T cells. PGE2 and IL-23 plus IL-1β synergistically induced early IL-17A secretion from CD161(+) CD4(+) memory T cells and the selective enrichment of IL-17A(+) CD161(+) CD4(+) memory T cells in culture. Conversely, IL-23 plus IL-1β partially opposed the PGE2-mediated repression of early interferon gamma (IFN-γ) secretion from CD161(+) cells, as well as the PGE2-mediated depletion of IFN-γ(+) CD161(+) cells. Our results suggest that PGE2 and IL-23 plus IL-1β induce the Th17 immune response preferentially in CD161(+) CD4(+) memory T cells, while divergently regulating their ability to express IFN-γ. We hypothesize that Th17-mediated chronic inflammation in IBD depends on the net response of CD161(+) CD4(+) memory T cells to both PGE2 and IL-23 plus IL-1β.     

An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2–dominated inflammatory response

In schistosomiasis, chronic parasite egg-induced granuloma formation can lead to tissue destruction and fibrosis, which causes much of the morbidity and mortality associated with this disease. Here we show the importance of IL-13 in the pathogenesis of schistosomiasis, and demonstrate, perhaps for the first time, the therapeutic efficacy of an IL-13 inhibitor, sIL-13Ralpha2-Fc, in the control of hepatic fibrosis. T-helper type 2 (Th2) cytokines dominate the immune response in mice infected with Schistosoma mansoni, yet the specific contributions of IL-13 and IL-4 to the development of fibrosis were not previously investigated. Our studies demonstrate that both cytokines play redundant roles in granuloma formation, which explains the ability of IL-4-deficient mice to form granulomas around eggs. More importantly, however, these studies demonstrate that IL-13 is the dominant Th2-type cytokine regulating fibrosis. IL-13 stimulated collagen production in fibroblasts, and procollagen I and procollagen III mRNA expression was decreased in sIL-13Ralpha2-Fc-treated mice. Moreover, the reduction in fibrosis observed in IL-4-deficient mice was much less pronounced than that in sIL-13Ralpha2-Fc-treated animals. Fibrosis is a major pathological manifestation of a number of allergic, autoimmune, and infectious diseases. Thus, our findings provide evidence that IL-13 inhibitors may be of general therapeutic benefit in preventing damaging tissue fibrosis resulting from Th2-dominated inflammatory responses.     

Helicobacter urease–induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma

Inflammasome activation and caspase-1–dependent (CASP1-dependent) processing and secretion of IL-1β and IL-18 are critical events at the interface of the bacterial pathogen Helicobacter pylori with its host. Whereas IL-1β promotes Th1 and Th17 responses and gastric immunopathology, IL-18 is required for Treg differentiation, H. pylori persistence, and protection against allergic asthma, which is a hallmark of H. pylori–infected mice and humans. Here, we show that inflammasome activation in DCs requires the cytoplasmic sensor NLRP3 as well as induction of TLR2 signaling by H. pylori. Screening of an H. pylori transposon mutant library revealed that pro–IL-1β expression is induced by LPS from H. pylori, while the urease B subunit (UreB) is required for NLRP3 inflammasome licensing. UreB activates the TLR2-dependent expression of NLRP3, which represents a rate-limiting step in NLRP3 inflammasome assembly. ureB-deficient H. pylori mutants were defective for CASP1 activation in murine bone marrow–derived DCs, splenic DCs, and human blood-derived DCs. Despite colonizing the murine stomach, ureB mutants failed to induce IL-1β and IL-18 secretion and to promote Treg responses. Unlike WT H. pylori, ureB mutants were incapable of conferring protection against allergen-induced asthma in murine models. Together, these results indicate that the TLR2/NLRP3/CASP1/IL-18 axis is critical to H. pylori–specific immune regulation.     

Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13–induced tissue responses and apoptosis

Mouse breast regression protein 39 (BRP-39; Chi3l1) and its human homologue YKL-40 are chitinase-like proteins that lack chitinase activity. Although YKL-40 is expressed in exaggerated quantities and correlates with disease activity in asthma and many other disorders, the biological properties of BRP-39/YKL-40 have only been rudimentarily defined. We describe the generation and characterization of BRP-39^−/− mice, YKL-40 transgenic mice, and mice that lack BRP-39 and produce YKL-40 only in their pulmonary epithelium. Studies of these mice demonstrated that BRP-39^−/− animals have markedly diminished antigen-induced Th2 responses and that epithelial YKL-40 rescues the Th2 responses in these animals. The ability of interleukin13 to induce tissue inflammation and fibrosis was also markedly diminished in the absence of BRP-39. Mechanistic investigations demonstrated that BRP-39 and YKL-40 play an essential role in antigen sensitization and immunoglobulin E induction, stimulate dendritic cell accumulation and activation, and induce alternative macrophage activation. These proteins also inhibit inflammatory cell apoptosis/cell death while inhibiting Fas expression, activating protein kinase B/AKT, and inducing Faim 3. These studies establish novel regulatory roles for BRP-39/YKL-40 in the initiation and effector phases of Th2 inflammation and remodeling and suggest that these proteins are therapeutic targets in Th2- and macrophage-mediated disorders.The evolutionarily conserved 18-glycosyl-hydrolase family contains true chitinases and molecules that lack chitinase activity (1–4). Much of the research in this area has focused on chitinases, like acidic mammalian chitinase (AMCase), that play critical roles in the life cycle of parasites (5, 6) and the pathogenesis of Th2 and antiparasite responses (3, 4, 7). However, the majority of the 18-glycosyl-hydrolase family members are chitinase-like proteins (CLPs), which, as a result of mutations in their highly conserved enzyme sites, do not contain chitinase activity. Breast regression protein 39 (BRP-39) and its human homologue YKL-40 (also called chitinase 3-like-1 and human cartilage glycoprotein [HcGP] 39) (8–10) are the prototypes of these enzymatically deficient CLPs. Surprisingly, their roles in biology have only been superficially addressed.BRP-39 and YKL-40 are produced by a variety of cells including neutrophils, monocytes, macrophages, chondrocytes, synovial cells, smooth muscle cells, endothelial cells, and tumor cells (3, 8, 11). Increased levels of YKL-40 protein and/or messenger RNA (mRNA) have been noted in patients with a broad spectrum of pathologies including bacterial infections, rheumatoid arthritis, osteoarthritis, giant cell arteritis, sarcoidosis, scleroderma, diabetes, atherosclerosis, inflammatory bowel disease, and solid malignancies (3, 8, 11–16). In many of these disorders, the levels of YKL-40 reflect the activity and natural history of the disease (2, 14–16). This is nicely illustrated in studies from our laboratory and from others, which have demonstrated that elevated levels of serum YKL-40 are seen in patients with asthma which correlate with the levels of lung tissue YKL-40 and disease severity (2). These studies also highlighted polymorphisms in chitinase 3-like-1 that correlated with the levels of circulating YKL-40, the presence of asthma, and compromised lung function (17). The potential importance of YKL-40 can also be seen in rheumatoid arthritis, coronary artery disease, solid cancers, and death in the elderly, where elevated serum YKL-40 levels correlate with the severity of joint involvement, the number of blocked coronary arteries, short disease-free intervals, and all-cause mortality, respectively (11, 14, 15, 18). As a result, YKL-40 is a prognostic biomarker and has been proposed to be a therapeutic target in conditions characterized by acute or chronic inflammation, extracellular matrix remodeling, fibrosis, and cancer (11, 18, 19). Because serum YKL-40 levels provide information that is different than that provided by established prognostic biomarkers, such as serum C-reactive protein, YKL-40 is believed to reflect different pathways in the pathogenesis of these disorders (11). However, our very limited understanding of the biology of BRP-39/YKL-40 makes it difficult to appreciate the true meaning of these disease-CLP associations and the ways that BRP-39 and YKL-40 contribute to normal biology and disease-relevant pathological responses. This is due, in part, to the fact that mice with null mutations of CLP and mice that overexpress CLP have not been generated, thereby limiting mouse modeling of these molecules. To address this deficiency and further define the biology of CLP, we generated and characterized mice with null mutations of BRP-39 (BRP-39^−/−), mice that overexpress YKL-40 in a lung-specific fashion, and mice that lack BRP-39 and produce YKL-40 only in their respiratory epithelium.