Retnla (Relmα/Fizz1) Suppresses Helminth-Induced Th2-Type Immunity

Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla−/− mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla−/− mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla−/− mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla−/− mice developed stronger Th2 responses, which could be reversed by exogenous rRelmα treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-γ, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses

Arginase-1–Expressing Macrophages Suppress Th2 Cytokine–Driven Inflammation and Fibrosis

Macrophage-specific expression of Arginase-1 is commonly believed to promote inflammation, fibrosis, and wound healing by enhancing L-proline, polyamine, and Th2 cytokine production. Here, however, we show that macrophage-specific Arg1 functions as an inhibitor of inflammation and fibrosis following infection with the Th2-inducing pathogen Schistosoma mansoni. Although susceptibility to infection was not affected by the conditional deletion of Arg1 in macrophages, Arg1−/flox;LysMcre mice died at an accelerated rate. The mortality was not due to acute Th1/NOS2-mediated hepatotoxicity or endotoxemia. Instead, granulomatous inflammation, liver fibrosis, and portal hypertension increased in infected Arg1−/flox;LysMcre mice. Similar findings were obtained with Arg1flox/flox;Tie2cre mice, which delete Arg1 in all macrophage populations. Production of Th2 cytokines increased in the infected Arg1−/flox;LysMcre mice, and unlike alternatively activated wild-type macrophages, Arg1−/flox;LysMcre macrophages failed to inhibit T cell proliferation in vitro, providing an underlying mechanism for the exacerbated Th2 pathology. The suppressive activity of Arg1-expressing macrophages was independent of IL-10 and TGF-β1. However, when exogenous L-arginine was provided, T cell proliferation was restored, suggesting that Arg1-expressing macrophages deplete arginine, which is required to sustain CD4+ T cell responses. These data identify Arg1 as the essential suppressive mediator of alternatively activated macrophages (AAM) and demonstrate that Arg1-expressing macrophages function as suppressors rather than inducers of Th2-dependent inflammation and fibrosis

Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent

Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4+ and γδ+ T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a−/− mice confirmed an essential role for IL-17A. Mechanistically, using ifnγ−/−, il10−/−, il10−/−il12p40−/−, and il10−/−il17a−/− mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is suppressed by IL-10 and facilitated by IFN-γ and IL-12/23p40. BLM-induced IL-17A production was also TGF-β dependent, and recombinant IL-17A–mediated fibrosis required TGF-β, suggesting cooperative roles for IL-17A and TGF-β in the development of fibrosis. Finally, we show that fibrosis induced by IL-1β, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1β were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis

Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis

Fibroproliferative diseases are driven by dysregulated tissue repair responses and are major cause of morbidity and mortality as they affect nearly every organ system. Type-2 cytokine responses are critically involved in tissue repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis are not well understood. Here, we have shown that the type-2 effector cytokine interleukin-13 simultaneously, yet independently, directed hepatic fibrosis and the compensatory proliferation of hepatocytes and biliary cells in progressive models of liver disease induced by interleukin-13 over-expression or following infection with Schistosoma mansoni. Using transgenic mice with interleukin-13 signaling genetically disrupted in hepatocytes, cholangiocytes, or resident tissue fibroblasts, we have revealed direct and distinct roles for interleukin-13 in fibrosis, steatosis, cholestasis, and ductular reaction. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis

Cationic Amino Acid Transporter-2 Regulates Immunity by Modulating Arginase Activity

Cationic amino acid transporters (CAT) are important regulators of NOS2 and ARG1 activity because they regulate L-arginine availability. However, their role in the development of Th1/Th2 effector functions following infection has not been investigated. Here we dissect the function of CAT2 by studying two infectious disease models characterized by the development of polarized Th1 or Th2-type responses. We show that CAT2−/− mice are significantly more susceptible to the Th1-inducing pathogen Toxoplasma gondii. Although T. gondii infected CAT2−/− mice developed stronger IFN-γ responses, nitric oxide (NO) production was significantly impaired, which contributed to their enhanced susceptibility. In contrast, CAT2−/− mice infected with the Th2-inducing pathogen Schistosoma mansoni displayed no change in susceptibility to infection, although they succumbed to schistosomiasis at an accelerated rate. Granuloma formation and fibrosis, pathological features regulated by Th2 cytokines, were also exacerbated even though their Th2 response was reduced. Finally, while IL-13 blockade was highly efficacious in wild-type mice, the development of fibrosis in CAT2−/− mice was largely IL-13-independent. Instead, the exacerbated pathology was associated with increased arginase activity in fibroblasts and alternatively activated macrophages, both in vitro and in vivo. Thus, by controlling NOS2 and arginase activity, CAT2 functions as a potent regulator of immunity

Charge compensation assisted enhancement of photoluminescence in combustion derived Li+ co-doped cubic ZrO2:Eu3+ nanophosphors

Red light emitting cubic Zr0.99Eu0.01O2:Li+ (0-9 mol%) nanoparticles are synthesized by a low temperature, self-propagating solution combustion method using oxalyl di-hydrazide (ODH) as fuel. In this study, we report systematic investigation of the effect of lithium ion (Li+) concentration on the structural properties and the photoluminescence of zirconia. With increasing lithium concentration, the crystallinity of the samples increases and the lattice strain decreases. The higher crystallinity is likely due to charge compensation achieved by replacing one Zr4+ ion by a Eu3+ and a Li+ ion. Scanning electron micrographs (SEM) reveal a mesoporous structure characteristic of combustion derived nanomaterials. Photoluminescence (PL) spectra show that the intensity of the red emission (606 nm) is highly dependent on Li+ ion concentration. Furthermore there is a promising enhancement in the associated lifetime. Upon Li+ doping, the PL intensity of the samples is found to increase by two fold compared to the undoped sample. Variation of PL intensity with Li+ concentration is attributed to the differences in probability of non-radiative recombination (relaxing). Intensity parameters (Omega(2), Omega) and radiative properties such as transition rates (A), branching ratios (beta), stimulated emission cross-section (sigma(e)), gain bandwidth (sigma(e) x Delta lambda(eff)) and optical gain (sigma(e) x tau) are calculated using the Judd-Ofelt theory. The calculated values suggest that in optimally co-doped samples, in addition to improved crystallinity and charge compensation, the lowering of Eu3+ site symmetry and the increase in the covalency of Eu-O bonding due to interstitial Li are responsible for the observed enhancement in PL intensity

TNF-α/IL-17 synergy inhibits IL-13 bioactivity via IL-13Rα2 induction

IL-17 and TNFα synergistically induce surface expression of IL-13Rα2 on primary lung fibroblasts, rendering them unresponsive to IL-13. Neutralizing antibodies to IL-13Rα2 restored IL-13-mediated signaling and transcriptome studies confirmed IL-13Rα2 is an IL-13 decoy receptor