Kidney-Specific Interleukin-17 Responses During Infection and Injury.

The kidneys are life-sustaining organs that are vital to removing waste from our body. Because of their anatomic position and high blood flow, the kidneys are vulnerable to damage due to infections and autoinflammatory conditions. Even now, our knowledge of immune responses in the kidney is surprisingly rudimentary. Studying kidney-specific immune events are challenging because of the poor regenerative capacity of the nephrons, accumulation of uremic toxins, and hypoxia- and arterial blood pressure-mediated changes, all of which have unexpected positive or negative impacts on the immune response in the kidney. Kidney-specific defense confers protection against pathogens. On the other hand, unresolved inflammation leads to kidney damage and fibrosis. Interleukin-17 is a proinflammatory cytokine that has been linked to immunity against pathogens and pathogenesis of autoinflammatory diseases. In this review, we discuss current knowledge of IL-17 activities in the kidney in the context of infections, autoinflammatory diseases, and renal fibrosis. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival.

Lymph-node (LN) stromal cell populations expand during the inflammation that accompanies T cell activation. Interleukin-17 (IL-17)-producing helper T cells (TH17 cells) promote inflammation through the induction of cytokines and chemokines in peripheral tissues. We demonstrate a critical requirement for IL-17 in the proliferation of LN and splenic stromal cells, particularly fibroblastic reticular cells (FRCs), during experimental autoimmune encephalomyelitis and colitis. Without signaling via the IL-17 receptor, activated FRCs underwent cell cycle arrest and apoptosis, accompanied by signs of nutrient stress in vivo. IL-17 signaling in FRCs was not required for the development of TH17 cells, but failed FRC proliferation impaired germinal center formation and antigen-specific antibody production. Induction of the transcriptional co-activator IκBζ via IL-17 signaling mediated increased glucose uptake and expression of the gene Cpt1a, encoding CPT1A, a rate-limiting enzyme of mitochondrial fatty acid oxidation. Hence, IL-17 produced by locally differentiating TH17 cells is an important driver of the activation of inflamed LN stromal cells, through metabolic reprogramming required to support proliferation and survival.

MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation.

Interleukin-17 (IL-17) induces pathology in autoimmunity and infections; therefore, constraint of this pathway is an essential component of its regulation. We demonstrate that the signaling intermediate MCPIP1 (also termed Regnase-1, encoded by Zc3h12a) is a feedback inhibitor of IL-17 receptor signal transduction. MCPIP1 knockdown enhanced IL-17-mediated signaling, requiring MCPIP1's endoribonuclease but not deubiquitinase domain. MCPIP1 haploinsufficient mice showed enhanced resistance to disseminated Candida albicans infection, which was reversed in an Il17ra(-/-) background. Conversely, IL-17-dependent pathology in Zc3h12a(+/-) mice was exacerbated in both EAE and pulmonary inflammation. MCPIP1 degraded Il6 mRNA directly but only modestly downregulated the IL-6 promoter. However, MCPIP1 strongly inhibited the Lcn2 promoter by regulating the mRNA stability of Nfkbiz, encoding the IκBζ transcription factor. Unexpectedly, MCPIP1 degraded Il17ra and Il17rc mRNA, independently of the 3' UTR. The cumulative impact of MCPIP1 on IL-6, IκBζ, and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.

Serum cytokine profiles of adults with idiopathic inflammatory myopathies.

OBJECTIVES: There is a paucity of available biomarkers of disease activity in idiopathic inflammatory myopathies (IIM), and serum cytokines/chemokines hold potential as candidate biomarkers. We aimed to determine serum cytokine profiles of IIM patients with active disease as compared to patients in remission and healthy controls. METHODS: The IIM patients with active disease (included patients enrolled in repository corticotropin injection trial), in remission, and healthy controls were enrolled in this cross-sectional observational study. Serum concentrations of 51 cytokines/chemokines were obtained by utilising a bead-based multiplex cytokine assay (Luminex®). The myositis core set measures were obtained for all the patients. Cytokines with the best predictive ability to differentiate these clinical groups were assessed with three methods: 1) Least Absolute Shrinkage and Selection Operator modelling, 2) stepwise approach, and 3) logistic regression model. RESULTS: Twenty-one IIM patients with active disease, 11 IIM patients in remission and 10 healthy controls were enrolled. Myositis patients had elevated levels of chemokines that attract eosinophils (eotaxin) and dendritic cells, NK cells, cytotoxic T-cells and monocytes/macrophages (CXCL-9, IP-10), cytokines that drive T-helper 1 responses (TNF-a, lymphotoxin-a), matrix degrading enzymes (MMP-3 and -9), and IGFBP-2 compared to healthy controls. Myositis patients with active disease had higher levels of lymphotoxin-a, CXCL-9, MIP-1a, MIP-1b and MMP-3 than patients in remission. CONCLUSIONS: This study demonstrated differences in cytokine profiles of IIM patients (active and inactive disease) compared to healthy controls and identified some cytokines that could potentially be used as biomarkers. Larger longitudinal studies are needed to validate our findings.

Arid5a Mediates an IL-17-Dependent Pathway That Drives Autoimmunity but Not Antifungal Host Defense.

IL-17 contributes to the pathogenesis of certain autoimmune diseases, but conversely is essential for host defense against fungi. Ab-based biologic drugs that neutralize IL-17 are effective in autoimmunity but can be accompanied by adverse side effects. Candida albicans is a commensal fungus that is the primary causative agent of oropharyngeal and disseminated candidiasis. Defects in IL-17 signaling cause susceptibility to candidiasis in mice and humans. A key facet of IL-17 receptor signaling involves RNA-binding proteins, which orchestrate the fate of target mRNA transcripts. In tissue culture models we showed that the RNA-binding protein AT-rich interaction domain 5A (Arid5a) promotes the stability and/or translation of multiple IL-17-dependent mRNAs. Moreover, during oropharyngeal candidiasis, Arid5a is elevated within the oral mucosa in an IL-17-dependent manner. However, the contribution of Arid5a to IL-17-driven events in vivo is poorly defined. In this study, we used CRISPR-Cas9 to generate mice lacking Arid5a. Arid5a -/- mice were fully resistant to experimental autoimmune encephalomyelitis, an autoimmune setting in which IL-17 signaling drives pathology. Surprisingly, Arid5a -/- mice were resistant to oropharyngeal candidiasis and systemic candidiasis, similar to immunocompetent wild-type mice and contrasting with mice defective in IL-17 signaling. Therefore, Arid5a-dependent signals mediate pathology in autoimmunity and yet are not required for immunity to candidiasis, indicating that selective targeting of IL-17 signaling pathway components may be a viable strategy for development of therapeutics that spare IL-17-driven host defense.

Divergent functions of IL-17-family cytokines in DSS colitis: Insights from a naturally-occurring human mutation in IL-17F.

The IL-17 family is structurally distinct from other cytokine subclasses. IL-17A and IL-17F, the most closely related of this family, form homodimers and an IL-17AF heterodimer. While IL-17A and IL-17F exhibit similar activities in many settings, in others their functions are divergent. To better understand the function of IL-17F in vivo, we created mice harboring a mutation in Il17f originally described in humans with unexplained chronic mucosal candidiasis (Ser-65-Leu). We evaluated Il17fS65L/S65L mice in DSS-colitis, as this is one of the few settings where IL-17A and IL-17F exhibit opposing activities. Specifically, IL-17A is protective of the gut epithelium, a finding that was revealed when trials of anti-IL-17A biologics in Crohn's disease failed and recapitulated in many mouse models of colitis. In contrast, mice lacking IL-17F are resistant to DSS-colitis, partly attributable to alterations in intestinal microbiota that mobilize Tregs. Here we report that Il17fS65L/S65L mice do not phenocopy Il17f-/- mice in DSS colitis, but rather exhibited a worsening disease phenotype much like Il17a-/- mice. Gut inflammation in Il17fS65L/S65L mice correlated with reduced Treg accumulation and lowered intestinal levels of Clostridium cluster XIV. Unexpectedly, the protective DSS-colitis phenotype in Il17f-/- mice could be reversed upon co-housing with Il17fS65L/S65L mice, also correlating with Clostridium cluster XIV levels in gut. Thus, the Il17fS65L/S65L phenotype resembles an IL-17A deficiency more closely than IL-17F deficiency in the setting of DSS colitis.

IL-17 in Renal Immunity and Autoimmunity.

The kidney is an organ particularly susceptible to damage caused by infections and autoimmune conditions. Renal inflammation confers protection against microbial infections. However, if unchecked, unresolved inflammation may lead to kidney damage. Although proinflammatory cytokine IL-17 is required for immunity against extracellular pathogens, dysregulated IL-17 response is also linked to autoimmunity. In this review, we will discuss the current knowledge of IL-17 activity in the kidney in context to renal immunity and autoimmunity and raise the intriguing question to what extent neutralization of IL-17 is beneficial or harmful to renal inflammation.

A Comparison of Acute Physiology and Chronic Health Evaluation II Score and Serum Procalcitonin Change for Predicting Mortality in Acute Pancreatitis.

INTRODUCTION: The prediction of mortality in acute pancreatitis (AP) is a useful estimate for effective treatment. Scoring systems such as acute physiology and chronic health evaluation (APACHE) II, computed tomography (CT) severity index (CTSI), bedside index of severity in acute pancreatitis (BISAP), etc., are used for prediction. Biomarkers like C-reactive protein (CRP) and procalcitonin (PCT) are also considered useful for prognostication. The aim of this retrospective study was to correlate the changes in serum PCT level with APACHE II score between admission and 48 hours as mortality predictor in AP. MATERIALS AND METHODS: The observational study was conducted in a cohort of 42 patients admitted consecutively in the seven-bedded general intensive care unit (ICU) of our institute between June 2016 and May 2018, with the diagnosis of AP. The APACHE II score and serum PCT level at admission and 48 hours were retrieved from the hospital database. The change in APACHE II and PCT level was compared between ICU "survivors" and "nonsurvivors." The predictive accuracy of APACHE II and PCT was measured using area under receiver-operator characteristics (ROC) curve. A p value <0.05 was considered as significant. RESULTS: Of the 42 patients enrolled, 30 patients (71.42%) were survivors and 12 (28.58%) were nonsurvivors. The median APACHE II score in nonsurvivors increased from 16 (7-19) to 23 (11-29) and remained unchanged at 16 (9-19 at admission; 10-22 at 48 hours) in survivors. The median PCT levels increased from 3.8 (1.2-5.6) to 6.2 (1.9-12.5) in nonsurvivors and decreased from 3.8 (1.2-5.6) to 2.2 (0.6-2.9) in survivors. Serum PCT change compared better than the APACHE II score change among survivors (r = 0.455, p = 0.011) with a mean (±standard deviation SD) change of 1.41 (±1.59). CONCLUSION: The change in serum PCT and APACHE II between admission and 48 hours correlates well and is useful for mortality prediction in AP. Serum PCT change compares better than APACHE II score change in survivors. HOW TO CITE THIS ARTICLE: Choudhuri AH, Duggal S, Biswas PS, Uppal R. A Comparison of Acute Physiology and Chronic Health Evaluation II Score and Serum Procalcitonin Change for Predicting Mortality in Acute Pancreatitis. Indian J Crit Care Med 2020;24(3):190-194.

A survey of physicians' appreciation and knowledge about airway safety measures in the wake of COVID-19 pandemic.

BACKGROUND AND AIMS: The implementation of safety measures during airway management is a major concern to prevent COVID-19 transmission during pandemic. Various guidelines and advisories are in vogue to ensure safe practices. However, their success depends on the caregivers' knowledge and understanding. This survey was conducted to assess the knowledge and safety concerns amongst physicians towards airway management in the background of COVID-19 pandemic. MATERIAL AND METHODS: A survey instrument of thirty questions covering three timelines of airway management viz. 'before', 'during' and 'after' airway intervention was created. The questionnaire was electronically mailed to the eligible physicians over a period of one month via a web-based platform and the responses were analyzed. The responses were depicted numerically as percentage. A multiple discriminant analysis was used to test the accuracy of responses after adjusting for common variables. RESULTS: Out of 407 responses, 300 were eligible for analysis. The respondents with correct answers to questions with single correct response were 46%, 69% and 57.3%, along the three timelines and the respondents with more than 75% correct responses in questions with multiple correct responses were 49%, 58% and 31% along the same timelines. About 75% of the participants became aware of transmission through aerosols aftermath pandemic. About two-third of the participants had knowledge about the safety guidelines and recommendations. Majority of the respondents were aware of the safety measures 'during airway intervention'. CONCLUSION: Our study found satisfactory knowledge and appreciable concern among the practicing physicians regarding airway safety measures in the wake of COVID-19 pandemic. However, more physicians were aware about the measures required to be adopted 'during' airway intervention. The survey highlights the need for a more focused training of the caregivers about safety measures 'before' and 'after' airway intervention.

Interleukin-17: Friend or foe in organ fibrosis.

Fibrosis affects all vital organs accounting for a staggering 45% of deaths worldwide and no effective therapies are currently available. Unresolved inflammation triggers downstream signaling events that lead to organ fibrosis. In recent years, proinflammatory cytokine Interleukin-17 (IL-17) has been implicated in several chronic inflammatory diseases that often culminate in organ damage followed by impaired wound healing and fibrosis. In this review, we outline the contribution of the IL-17 in mediating fibrotic diseases in various organs. A comprehensive understanding of the inflammatory events, and particularly the details of IL-17 signaling in vivo, could be beneficial in designing new therapeutic or preventive approaches to treat fibrosis. Additionally, understanding organ-specific differences in IL-17 activity could lead to targeted therapies and help spare other organs from unwanted side effects.

Back to the future: revisiting MAS as a tool for modern plant breeding.

KEY MESSAGE: New models for integration of major gene MAS with modern breeding approaches stand to greatly enhance the reliability and efficiency of breeding, facilitating the leveraging of traditional genetic diversity. Genetic diversity is well recognised as contributing essential variation to crop breeding processes, and marker-assisted selection is cited as the primary tool to bring this diversity into breeding programs without the associated genetic drag from otherwise poor-quality genomes of donor varieties. However, implementation of marker-assisted selection techniques remains a challenge in many breeding programs worldwide. Many factors contribute to this lack of adoption, such as uncertainty in how to integrate MAS with traditional breeding processes, lack of confidence in MAS as a tool, and the expense of the process. However, developments in genomics tools, locus validation techniques, and new models for how to utilise QTLs in breeding programs stand to address these issues. Marker-assisted forward breeding needs to be enabled through the identification of robust QTLs, the design of reliable marker systems to select for these QTLs, and the delivery of these QTLs into elite genomic backgrounds to enable their use without associated genetic drag. To enhance the adoption and effectiveness of MAS, rice is used as an example of how to integrate new developments and processes into a coherent, efficient strategy for utilising genetic variation. When processes are instituted to address these issues, new genes can be rolled out into a breeding program rapidly and completely with a minimum of expense.

Enhancing the rate of genetic gain in public-sector plant breeding programs: lessons from the breeder's equation.

KEY MESSAGE: The integration of new technologies into public plant breeding programs can make a powerful step change in agricultural productivity when aligned with principles of quantitative and Mendelian genetics. The breeder's equation is the foundational application of quantitative genetics to crop improvement. Guided by the variables that describe response to selection, emerging breeding technologies can make a powerful step change in the effectiveness of public breeding programs. The most promising innovations for increasing the rate of genetic gain without greatly increasing program size appear to be related to reducing breeding cycle time, which is likely to require the implementation of parent selection on non-inbred progeny, rapid generation advance, and genomic selection. These are complex processes and will require breeding organizations to adopt a culture of continuous optimization and improvement. To enable this, research managers will need to consider and proactively manage the, accountability, strategy, and resource allocations of breeding teams. This must be combined with thoughtful management of elite genetic variation and a clear separation between the parental selection process and product development and advancement process. With an abundance of new technologies available, breeding teams need to evaluate carefully the impact of any new technology on selection intensity, selection accuracy, and breeding cycle length relative to its cost of deployment. Finally breeding data management systems need to be well designed to support selection decisions and novel approaches to accelerate breeding cycles need to be routinely evaluated and deployed.

Loss of Twist1 in the Mesenchymal Compartment Promotes Increased Fibrosis in Experimental Lung Injury by Enhanced Expression of CXCL12.

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by the accumulation of apoptosis-resistant fibroblasts in the lung. We have previously shown that high expression of the transcription factor Twist1 may explain this prosurvival phenotype in vitro. However, this observation has never been tested in vivo. We found that loss of Twist1 in COL1A2+ cells led to increased fibrosis characterized by very significant accumulation of T cells and bone marrow-derived matrix-producing cells. We found that Twist1-null cells expressed high levels of the T cell chemoattractant CXCL12. In vitro, we found that the loss of Twist1 in IPF lung fibroblasts increased expression of CXCL12 downstream of increased expression of the noncanonical NF-κB transcription factor RelB. Finally, blockade of CXCL12 with AMD3100 attenuated the exaggerated fibrosis observed in Twist1-null mice. Transcriptomic analysis of 134 IPF patients revealed that low expression of Twist1 was characterized by enrichment of T cell pathways. In conclusion, loss of Twist1 in collagen-producing cells led to increased bleomycin-induced pulmonary fibrosis, which is mediated by increased expression of CXCL12. Twist1 expression is associated with dysregulation of T cells in IPF patients. Twist1 may shape the IPF phenotype and regulate inflammation in fibrotic lung injury.

Epidemiology of Multidrug Resistant Infections after Inter-ICU Transfer in India.

BACKGROUND AND AIMS: The patients in the intensive care unit (ICU) are often infected with multidrug resistant (MDR) organisms. When they are transferred to other ICUs, they can expand the reservoir of MDR organisms and pose a threat to the infection control program. The present observational study was undertaken to describe the epidemiology and compare the outcome of MDR and non-MDR infections after inter ICU patient transfer. MATERIALS AND METHODS: A retrospective study was conducted in a cohort of 134 consecutive admitted patients in a tertiary care ICU from other ICUs. The primary objective was to measure the prevalence of MDR and non-MDR infections. The secondary objective was to compare the outcome between MDR and non-MDR group and identify the factors independently associated with mortality for each group. RESULTS: Among 134 patients, 89 had infections (66.4%) and in 29 (21.6%) were due to MDR organisms. The most common organism was Klebsiella in the MDR and E. coli in the non-MDR group. There was no difference between the groups in mortality, duration of mechanical ventilation and length of ICU stay. The duration of mechanical ventilation and ICU stay >7 days was independently associated with mortality in the MDR group. No association was found in the non-MDR group. CONCLUSION: The study demonstrates a high prevalence of MDR infections after inter ICU transfer. There is no difference in outcome between the groups, but the mortality in the MDR group is independently associated with a longer duration of mechanical ventilation and ICU stay. HOW TO CITE THIS ARTICLE: Choudhuri AH, Ahuja B, Biswas PS, Uppal R. Epidemiology of Multidrug Resistant Infections after Inter-ICU Transfer in India. Indian Journal of Critical Care Medicine, January 2019;23(1):1-6.

The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney.

The incidence of life-threatening disseminated Candida albicans infections is increasing in hospitalized patients, with fatalities as high as 60%. Death from disseminated candidiasis in a significant percentage of cases is due to fungal invasion of the kidney, leading to renal failure. Treatment of candidiasis is hampered by drug toxicity, the emergence of antifungal drug resistance and lack of vaccines against fungal pathogens. IL-17 is a key mediator of defense against candidiasis. The underlying mechanisms of IL-17-mediated renal immunity have so far been assumed to occur solely through the regulation of antimicrobial mechanisms, particularly activation of neutrophils. Here, we identify an unexpected role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in C. albicans-infected kidney, and we show that the KKS provides significant renal protection in candidiasis. Microarray data indicated that Klk1 was upregulated in infected kidney in an IL-17-dependent manner. Overexpression of Klk1 or treatment with bradykinin rescued IL-17RA-/- mice from candidiasis. Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection. Furthermore, combining a minimally effective dose of fluconazole with bradykinin markedly improved survival compared to either drug alone. These results indicate that IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the KKS. Since drugs targeting the KKS are approved clinically, these findings offer potential avenues for the treatment of this fatal nosocomial infection.

IL-17 Receptor Signaling Negatively Regulates the Development of Tubulointerstitial Fibrosis in the Kidney.

Chronic inflammation has an important role in the development and progression of most fibrotic diseases, for which no effective treatments exist. Tubulointerstitial fibrosis (TF) is characterized by irreversible deposition of fibrous tissue in chronic kidney diseases. Prolonged injurious stimuli and chronic inflammation regulate downstream events that lead to TF. In recent years, interleukin-17 (IL-17) has been strongly linked to organ fibrosis. However, the role of IL-17 receptor signaling in TF is an active area of debate. Using the unilateral ureteral obstruction (UUO) mouse model of TF, we show that IL-17 receptor A-deficient mice (Il17ra-/- ) exhibit increased TF in the obstructed kidney. Consequently, overexpression of IL-17 restored protection in mice with UUO. Reduced renal expression of matrix-degrading enzymes results in failure to degrade ECM proteins, thus contributing to the exaggerated TF phenotype in Il17ra -/- mice. We demonstrate that the antifibrotic kallikrein-kinin system (KKS) is activated in the obstructed kidney in an IL-17-dependent manner. Accordingly, Il17ra-/- mice receiving bradykinin, the major end-product of KKS activation, prevents TF development by upregulating the expression of matrix-degrading enzymes. Finally, we show that treatment with specific agonists for bradykinin receptor 1 or 2 confers renal protection against TF. Overall, our results highlight an intriguing link between IL-17 and activation of KKS in protection against TF, the common final outcome of chronic kidney conditions leading to devastating end-stage renal diseases.

Delinking CARD9 and IL-17: CARD9 Protects against Candida tropicalis Infection through a TNF-α-Dependent, IL-17-Independent Mechanism.

Candida is the third most common cause of bloodstream infections in hospitalized patients. Immunity to C. albicans, the most frequent species to be isolated in candidiasis, involves a well-characterized Dectin-1/caspase-associated recruitment domain adaptor 9 (CARD9)/IL-17 signaling axis. Infections caused by non-albicans Candida species are on the rise, but surprisingly little is known about immunity to these pathogens. In this study, we evaluated a systemic infection model of C. tropicalis, a clinically relevant, but poorly understood, non-albicans Candida. Mice lacking CARD9 were profoundly susceptible to C. tropicalis, displaying elevated fungal burdens in visceral organs and increased mortality compared with wild-type (WT) controls. Unlike C. albicans, IL-17 responses were induced normally in CARD9(-/-) mice following C. tropicalis infection. Moreover, there was no difference in susceptibility to C. tropicalis infection between WT and IL-23p19(-/-), IL-17RA(-/-), or Act1(-/-) mice. However, TNF-α expression was markedly impaired in CARD9(-/-) mice. Consistently, WT mice depleted of TNF-α were more susceptible to C. tropicalis, and CARD9-deficient neutrophils and monocytes failed to produce TNF-α following stimulation with C. tropicalis Ags. Both neutrophils and monocytes were necessary for defense against C. tropicalis, because their depletion in WT mice enhanced susceptibility to C. tropicalis. Disease in CARD9(-/-) mice was not due to defective neutrophil or monocyte recruitment to infected kidneys. However, TNF-α treatment of neutrophils in vitro enhanced their ability to kill C. tropicalis. Thus, protection against systemic C. tropicalis infection requires CARD9 and TNF-α, but not IL-17, signaling. Moreover, CARD9-dependent production of TNF-α enhances the candidacidal capacity of neutrophils, limiting fungal disease during disseminated C. tropicalis infection.

Expression of RXFP1 Is Decreased in Idiopathic Pulmonary Fibrosis. Implications for Relaxin-based Therapies.

RATIONALE: Relaxin is a hormone that has been considered as a potential therapy for patients with fibrotic diseases. OBJECTIVES: To gauge the potential efficacy of relaxin-based therapies in idiopathic pulmonary fibrosis (IPF), we studied gene expression for relaxin/insulin-like family peptide receptor 1 (RXFP1) in IPF lungs and controls. METHODS: We analyzed gene expression data obtained from the Lung Tissue Research Consortium and correlated RXFP1 gene expression data with cross-sectional clinical and demographic data. We also employed ex vivo donor and IPF lung fibroblasts to test RXFP1 expression in vitro. We tested CGEN25009, a relaxin-like peptide, in lung fibroblasts and in bleomycin injury. MEASUREMENTS AND MAIN RESULTS: We found that RXFP1 is significantly decreased in IPF. In patients with IPF, the magnitude of RXFP1 gene expression correlated directly with diffusing capacity of the lung for carbon monoxide (P < 0.0001). Significantly less RXFP1 was detected in vitro in IPF fibroblasts than in donor controls. Transforming growth factor-ß decreased RXFP1 in both donor and IPF lung fibroblasts. CGEN25009 was effective at decreasing bleomycin-induced, acid-soluble collagen deposition in vivo. The relaxin-like actions of CGEN25009 were abrogated by RXFP1 silencing in vitro, and, in comparison with donor lung fibroblasts, IPF lung fibroblasts exhibited decreased sensitivity to the relaxin-like effects of CGEN25009. CONCLUSIONS: IPF is characterized by the loss of RXFP1 expression. RXFP1 expression is directly associated with pulmonary function in patients with IPF. The relaxin-like effects of CGEN25009 in vitro are dependent on expression of RXFP1. Our data suggest that patients with IPF with the highest RXFP1 expression would be predicted to be most sensitive to relaxin-based therapies.

Interleukin 17 signaling drives Type I Interferon induced proliferative crescentic glomerulonephritis in lupus-prone mice.

Crescentic glomerulonephritis (cGN) is a severe clinical manifestation in a subset of patients with Systemic lupus erythematosus. Lack of understanding of the pathogenesis of cGN act as a major constraint in treating these patients. Emerging evidence suggest a critical role of IL-17 in the pathogenesis of membranoproliferative glomerulonephritis in lupus. However, the role of IL-17 receptor (IL-17RA) signaling in cGN is unknown. Here, we developed a model of poly I:C-induced Type I Interferon (IFN-I)-dependent cGN in B6.MRL-Faslpr/J (B6.lpr) mice. B6.lpr mice deficient in IL-17RA were protected from IFN-I-dependent cGN. While systemic response was unabated, renal infiltration of alternatively activated macrophages was severely impaired in IL-17RA(-/-) mice. Finally, we show that IL-17 differentially regulates the expression of macrophage chemo-attractant genes in renal tubular epithelial cells and macrophages in association with IFN-I. These results suggest that neutralization IL-17 may confer better protection in SLE patients with high IFN-I gene signature and cGN.

Emerging roles of the Th17/IL-17-axis in glomerulonephritis.

Different T cell subsets have been implicated in the pathogenesis of glomerulonephritis. Several lines of evidence indicate the recently identified interleukin-17 (IL-17)-producing T cells (Th17 cells) to be involved in the renal inflammatory cascade associated with glomerulonephritis. In this review we outline different forms of glomerulonephritis and the contribution of the Th17/IL-17-axis in mediating the downstream effects and pathology associated with the disease. Learning more about the Th17/IL-17-axis can help to develop promising therapeutic strategy for the treatment of various forms of glomerulonephritis.