[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-22 is a member of the IL-10 family of cytokines that has been extensively studied since its discovery in 2000. This review article aims to describe the cellular sources and signaling pathways of this cytokine as well as the functions of IL-22 in the intestine. In addition, this article describes the roles of IL-22 in the pathogenesis of several gastrointestinal diseases, including inhibition of inflammation and barrier defense against pathogens within the intestine. Since many of the functions of IL-22 in the intestine are incompletely understood, this review is meant to assess our current understanding of the roles of IL-22 and provide new opportunities for inquiry to improve human intestinal health and disease.
Full-text · Article · Jan 2016 · Frontiers in Cell and Developmental Biology
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-22 is an IL-10-related cytokine produced by T helper (Th) 17 cells and other immune cells that signals via
IL-22 receptor alpha 1 which is expressed on epithelial tissues as well as hepatocytes. IL-22 has been shown to have hepatoprotective
effects that are mediated by STAT3 signaling. However, it is unclear if IL-22 can directly regulate antimicrobial programs
in the liver. To test this hypothesis, hepatocyte-specific IL-22Ra1 knockout (Il22Ra1Hep-/-) and Stat3 knockout (Stat3Hep-/-) mice were generated and subjected to intraabdominal infection with Klebsiella pneumoniae (K. pneumoniae) that results in liver injury and necrosis. We found that overexpression of IL-22 or therapeutic administration of rIL-22,
given two hours post-infection, significantly reduced bacterial burden in both the liver and spleen. The antimicrobial activity
of rIL-22 required hepatic Il22Ra1 and Stat3. Serum from rIL-22 treated mice showed potent bacteriostatic activity against K. pneumoniae, which was dependent on lipocalin-2 (LCN2). However, in vivo, rIL-22 induced antimicrobial activity was only partially reduced in LCN2 deficient mice. We found that rIL-22 also induced
serum amyloid A2 (SAA2) and SAA2 had anti-K. pneumoniae bactericidal activity in vitro. These results demonstrate that IL-22, through IL-22RA1 and STAT3 singling, can induce liver intrinsic antimicrobial activity,
which is in part due to LCN2 and SAA2. Therefore, IL-22 may be a useful adjunct in treating hepatic and intra-abdominal infections.
No preview · Article · Jan 2016 · Infection and immunity
[Show abstract][Hide abstract] ABSTRACT: Bacterial pneumonia and tracheobronchitis are diagnosed frequently following lung transplantation. The diseases share clinical signs of inflammation and are often difficult to differentiate based on culture results. Microbiome and host immune response signatures that distinguish between pneumonia and tracheobronchitis are undefined. Using a retrospective study design, we selected 49 bronchoalveolar lavage fluid samples from 16 lung transplant recipients diagnosed with pneumonia (n=8), tracheobronchitis (n=12) or colonization without respiratory infection (n=29). We ensured an even distribution of Pseudomonas aeruginosa or Staphylococcus aureus culture-positive samples across the groups. Bayesian regression analysis identified non-culture based signatures comprising 16S rRNA microbiome profiles, cytokine levels, and clinical variables that characterized the three diagnoses. Relative to samples associated with colonization, those from pneumonia had significantly lower microbial diversity, decreased levels of several bacterial genera, and prominent multifunctional cytokine responses. In contrast, tracheobronchitis was characterized by high microbial diversity and multifunctional cytokine responses that differed from those of pneumonia-colonization comparisons. The dissimilar microbiomes and cytokine responses underlying bacterial pneumonia and tracheobronchitis following lung transplantation suggest that the diseases result from different pathogenic processes. Microbiomes and cytokine responses had complementary features, suggesting that they are closely inter-connected in the pathogenesis of both diseases. This article is protected by copyright. All rights reserved.
No preview · Article · Dec 2015 · American Journal of Transplantation
[Show abstract][Hide abstract] ABSTRACT: Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1-expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1-expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB.
Full-text · Article · Nov 2015 · Journal of Clinical Investigation
[Show abstract][Hide abstract] ABSTRACT: Mesenchymal stem cells (MSCs) and macrophages are fundamental components of the stem cell niche and function coordinately to regulate haematopoietic stem cell self-renewal and mobilization. Recent studies indicate that mitophagy and healthy mitochondrial function are critical to the survival of stem cells, but how these processes are regulated in MSCs is unknown. Here we show that MSCs manage intracellular oxidative stress by targeting depolarized mitochondria to the plasma membrane via arrestin domain-containing protein 1-mediated microvesicles. The vesicles are then engulfed and re-utilized via a process involving fusion by macrophages, resulting in enhanced bioenergetics. Furthermore, we show that MSCs simultaneously shed micro RNA-containing exosomes that inhibit macrophage activation by suppressing Toll-like receptor signalling, thereby de-sensitizing macrophages to the ingested mitochondria. Collectively, these studies mechanistically link mitophagy and MSC survival with macrophage function, thereby providing a physiologically relevant context for the innate immunomodulatory activity of MSCs.
Full-text · Article · Oct 2015 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: Studies over the last two decades have revealed profound immunomodulatory aspects of vitamin D on various aspects of the immune system. This review will provide an overview of Vitamin D metabolism, a description of dendritic cell subsets, and highlight recent advances on the effects of vitamin D on dendritic cell function, maturation, cytokine production and antigen presentation. The active form of vitamin D, 1,25(OH)₂D₃, has important immunoregulatory and anti-inflammatory effects. Specifically, the 1,25(OH)₂D₃-Vitamin D₃ complex can affect the maturation and migration of many dendritic cell subsets, conferring a special immunoregulatory role as well as tolerogenic properties affecting cytokine and chemokine production. Furthermore, there have been many recent studies demonstrating the effects of Vitamin D on allergic disease and autoimmunity. A clear understanding of the effects of the various forms of Vitamin D will provide new opportunities to improve human health.
[Show abstract][Hide abstract] ABSTRACT: Asthma is a heterogeneous disease whose etiology is poorly understood but is likely to involve innate responses to inhaled microbial components that are found in allergens. The influence of these components on pulmonary inflammation has been largely studied in the context of individual agonists, despite knowledge that they can have synergistic effects when used in combination. Here we have explored the effects of LPS and β-glucan, two commonly-encountered microbial agonists, on the pathogenesis of allergic and non-allergic respiratory responses to house dust mite allergen. Notably, sensitization with these microbial components in combination acted synergistically to promote robust neutrophilic inflammation, which involved both Dectin-1 and TLR-4. This pulmonary neutrophilic inflammation was corticosteroid-refractory, resembling that found in patients with severe asthma. Thus our results provide key new insights into how microbial components influence the development of respiratory pathology.
[Show abstract][Hide abstract] ABSTRACT: Asthma is a common chronic disease without cure. Our understanding of asthma onset, pathobiology, classification and management has evolved substantially over the past decade; however, significant asthma-related morbidity and excess healthcare utilization and cost persist. To address this important clinical condition, the National Heart, Lung, and Blood Institute (NHLBI) convened a group of extramural investigators for an Asthma Research Strategic Planning workshop on September 18-19, 2014 to accelerate discoveries and their translation to patients. The workshop focused on (1) in utero and early life origins of asthma, (2) the use of phenotypes and endotypes to classify disease, (3) defining disease modification, (4) disease management, and (5) implementation research. This report summarizes the workshop, producing recommendations to guide future research in asthma.
Full-text · Article · Aug 2015 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Pneumocystis pneumonia remains a common opportunistic infection in the diverse immunosuppressed population. One clear risk factor for susceptibility to Pneumocystis is a declining CD4+ T cell count in the setting of HIV/AIDS or primary immunodeficiency. Non-HIV-infected individuals taking immunosuppressive drug regimens targeting T cell activation are also susceptible. Given the crucial role of CD4+ T cells in host defense against Pneumocystis, we used RNA sequencing of whole lung early in infection in wildtype and CD4-depleted animals as an unbiased approach to examine mechanisms of fungal clearance. In wild-type mice, a strong eosinophil signature was observed at day 14 post Pneumocystis challenge, and eosinophils were increased in the bronchoalveolar lavage fluid of wild-type mice. Furthermore, eosinophilopoiesis-deficient Gata1tm6Sho/J mice were more susceptible to Pneumocystis infection when compared with BALB/c controls, and bone marrow-derived eosinophils had in vitro Pneumocystis killing activity. To drive eosinophilia in vivo, Rag1-/- mice were treated with a plasmid expressing IL-5 (pIL5) or an empty plasmid control via hydrodynamic injection. The pIL5-treated mice had increased serum IL-5 and eosinophilia in the lung, as well as reduced Pneumocystis burden, compared with mice treated with control plasmid. In addition, pIL5 treatment could induce eosinophilia and reduce Pneumocystis burden in CD4-depleted C57BL/6 and BALB/c mice, but not eosinophilopoiesis-deficient Gata1tm6Sho/J mice. Taken together, these results demonstrate that an early role of CD4+ T cells is to recruit eosinophils to the lung and that eosinophils are a novel candidate for future therapeutic development in the treatment of Pneumocystis pneumonia in the immunosuppressed population.
No preview · Article · Jul 2015 · The Journal of Immunology
[Show abstract][Hide abstract] ABSTRACT: Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng-/- mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra-/- mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.
Preview · Article · Jun 2015 · The Journal of clinical investigation