RESUMO
Influenza A virus (IAV) infection leads to the formation of mucosal memory CD4 T cells that can protect the host. An in-depth understanding of the signals that shape memory cell development is required for more effective vaccine design. We have examined the formation of memory CD4 T cells in the lung following IAV infection of mice, characterizing changes to the lung landscape and immune cell composition. IAV-specific CD4 T cells were found throughout the lung at both primary and memory time points. These cells were found near lung airways and in close contact with a range of immune cells including macrophages, dendritic cells, and B cells. Interactions between lung IAV-specific CD4 T cells and major histocompatibility complex (MHC)II+ cells during the primary immune response were important in shaping the subsequent memory pool. Treatment with an anti-MHCII blocking antibody increased the proportion of memory CD4 T cells found in lung airways but reduced interferon-γ expression by IAV-specific immunodominant memory CD4 T cells. The immunodominant CD4 T cells expressed higher levels of programmed death ligand 1 (PD1) than other IAV-specific CD4 T cells and PD1+ memory CD4 T cells were located further away from MHCII+ cells than their PD1-low counterparts. This distinction in location was lost in mice treated with anti-MHCII antibodies. These data suggest that sustained antigen presentation in the lung impacts the formation of memory CD4 T cells by regulating their cytokine production and location.
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Interferon gamma (IFNγ) is a potent antiviral cytokine that can be produced by many innate and adaptive immune cells during infection. Currently, our understanding of which cells produce IFNγ and where they are located at different stages of an infection is limited. We have used reporter mice to investigate in vivo expression of Ifnγ mRNA in the lung and secondary lymphoid organs during and following influenza A virus (IAV) infection. We observed a triphasic production of Ifnγ expression. Unconventional T cells and innate lymphoid cells, particularly NK cells, were the dominant producers of early Ifnγ, while CD4 and CD8 T cells were the main producers by day 10 post-infection. Following viral clearance, some memory CD4 and CD8 T cells continued to express Ifnγ in the lungs and draining lymph node. Interestingly, Ifnγ production by lymph node natural killer (NK), NKT, and innate lymphoid type 1 cells also continued to be above naïve levels, suggesting memory-like phenotypes for these cells. Analysis of the localization of Ifnγ+ memory CD4 and CD8 T cells demonstrated that cytokine+ T cells were located near airways and in the lung parenchyma. Following a second IAV challenge, lung IAV-specific CD8 T cells rapidly increased their expression of Ifnγ while CD4 T cells in the draining lymph node increased their Ifnγ response. Together, these data suggest that Ifnγ production fluctuates based on cellular source and location, both of which could impact subsequent immune responses.
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Spillover events of avian influenza A viruses (IAVs) to humans could represent the first step in a future pandemic1. Several factors that limit the transmission and replication of avian IAVs in mammals have been identified. There are several gaps in our understanding to predict which virus lineages are more likely to cross the species barrier and cause disease in humans1. Here, we identified human BTN3A3 (butyrophilin subfamily 3 member A3)2 as a potent inhibitor of avian IAVs but not human IAVs. We determined that BTN3A3 is expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts primarily at the early stages of the virus life cycle by inhibiting avian IAV RNA replication. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F or, rarely, 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, avian IAV serotypes, such as H7 and H9, that spilled over into humans also evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure3. Thus, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.
Assuntos
Aves , Interações entre Hospedeiro e Microrganismos , Vírus da Influenza A , Influenza Aviária , Influenza Humana , Zoonoses Virais , Animais , Humanos , Aves/virologia , Vírus da Influenza A/classificação , Vírus da Influenza A/genética , Vírus da Influenza A/crescimento & desenvolvimento , Vírus da Influenza A/isolamento & purificação , Influenza Aviária/transmissão , Influenza Aviária/virologia , Influenza Humana/prevenção & controle , Influenza Humana/transmissão , Influenza Humana/virologia , Primatas , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Medição de Risco , Zoonoses Virais/prevenção & controle , Zoonoses Virais/transmissão , Zoonoses Virais/virologia , Replicação ViralRESUMO
The lung is frequently and repeatedly exposed to invading pathogens and thus requires constant immunosurveillance. Professional antigen presenting cells (APCs), including dendritic cells, engulf invading pathogens and present their peptides via major histocompatibility complexes (MHC) I and II, to CD8 or CD4 T cells. Epithelial cells and stromal cells (including fibroblasts) provide more than structural support, they are increasingly recognised as key players in the immune response, acting as non-professional APCs through interactions with antigen experienced T cells that migrate to the lung. The importance of the contributions of non-professional and professional APCs to T cell function in vivo, is currently unclear. This review summarises the roles of professional and non-professional APCs in lung immunity, at the steady state and following viral insult, with particular emphasis on their ability to interact with and influence T cells.
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Apresentação de Antígeno , Células Apresentadoras de Antígenos , Humanos , Linfócitos T CD4-Positivos , Pulmão , Complexo Principal de HistocompatibilidadeRESUMO
Communication between stromal and immune cells is essential to maintain tissue homeostasis, mount an effective immune response and promote tissue repair. This 'crosstalk' occurs in both the steady state and following a variety of insults, for example, in response to local injury, at sites of infection or cancer. What do we mean by crosstalk between cells? Reciprocal activation and/or regulation occurs between immune and stromal cells, by direct cell contact and indirect mechanisms, including the release of soluble cytokines. Moving beyond cell-to-cell contact, this review investigates the complexity of 'cross-space' cellular communication. We highlight different examples of cellular communication by a variety of lung stromal and immune cells following tissue insults. This review examines how the 'geography of the lung microenvironment' is altered in various disease states; more specifically, we investigate how this influences lung epithelial cells and fibroblasts via their communication with immune cells and each other.
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Linfócitos T CD8-Positivos/imunologia , Células Epiteliais/imunologia , Fibroblastos/imunologia , Pulmão/patologia , Células Estromais/imunologia , Animais , Comunicação Celular , Microambiente Celular , Humanos , Imunidade CelularRESUMO
Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-ß1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in RelΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.
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Epitélio/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Macrófagos/patologia , Proteínas Proto-Oncogênicas c-rel/genética , Animais , Polaridade Celular/genética , Marcação de Genes , Hepatócitos/patologia , Hidroxiprolina/metabolismo , Cirrose Hepática/prevenção & controle , Regeneração Hepática/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitose/genética , Comunicação Parácrina/genética , Fosfofrutoquinase-2/genética , Proteínas Proto-Oncogênicas c-rel/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-rel/metabolismoRESUMO
CXC chemokine receptor 3 (CXCR3) A and its IFN-inducible ligands CXCL9 and CXCL10 regulate vascular remodeling and fibroblast motility. IL-13 is a profibrotic cytokine implicated in the pathogenesis of inflammatory and fibroproliferative conditions. Previous work from our laboratory has shown that CXCR3A is negatively regulated by IL-13 and is necessary for the basal regulation of the IL-13 receptor subunit IL-13Rα2. This study investigates the regulation of fibroblast phenotype, function, and downstream IL-13 signaling by CXCR3A in vitro. CXCR3A was overexpressed via transient transfection. CXCR3A-/- lung fibroblasts were isolated for functional analysis. Additionally, the contribution of CXCR3A to tissue remodeling following acute lung injury was assessed in vivo with wild-type (WT) and CXCR3-/- mice challenged with IL-13. CXCR3 and IL-13Rα2 displayed a reciprocal relationship after stimulation with either IL-13 or CXCR3 ligands. CXCR3A reduced expression of fibroblast activation makers, soluble collagen production, and proliferation. CXCR3A enhanced the basal expression of pERK1/2 while inducing IL-13-mediated downregulation of NF-κB-p65. CXCR3A-/- pulmonary fibroblasts were increasingly proliferative and displayed reduced contractility and α-smooth muscle actin expression. IL-13 challenge regulated expression of the CXCR3 ligands and soluble IL-13Rα2 levels in lungs and bronchoalveolar lavage fluid (BALF) of WT mice; this response was absent in CXCR3-/- mice. Alveolar macrophage accumulation and expression of genes involved in lung remodeling was increased in CXCR3-/- mice. We conclude that CXCR3A is a central antifibrotic factor in pulmonary fibroblasts, limiting fibroblast activation and reducing extracellular matrix (ECM) production. Therefore, targeting of CXCR3A may be a novel approach to regulating fibroblast activity in lung fibrosis and remodeling.
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Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Fibrose Pulmonar/patologia , Receptores CXCR3/metabolismo , Células 3T3 , Animais , Linhagem Celular , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Interleucina-13/genética , Interleucina-13/metabolismo , Subunidade alfa2 de Receptor de Interleucina-13/genética , Pulmão/citologia , Pulmão/metabolismo , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fator de Transcrição RelA/metabolismoRESUMO
Systemic Sclerosis (SSc) is an autoimmune idiopathic connective tissue disease, characterized by aberrant fibro-proliferative and inflammatory responses, causing fibrosis of multiple organs. In recent years the interactions between innate and adaptive immune cells with resident fibroblasts have been uncovered. Cross-talk between immune and stromal cells mediates activation of stromal cells to myofibroblasts; key cells in the pathophysiology of fibrosis. These cells and their cytokines appear to mediate their effects in both a paracrine and autocrine fashion. This review examines the role of innate and adaptive immune cells in SSc, focusing on recent advances that have illuminated our understanding of ongoing bi-directional communication between immune and stromal cells. Finally, we appraise current and future therapies and how these may be useful in a disease that currently has no specific disease modifying treatment.
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Linfócitos B/imunologia , Comunicação Celular/imunologia , Miofibroblastos/imunologia , Escleroderma Sistêmico/imunologia , Linfócitos T/imunologia , Animais , Linfócitos B/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Retroalimentação Fisiológica , Humanos , Imunidade Inata , Miofibroblastos/metabolismo , Escleroderma Sistêmico/sangue , Transdução de Sinais/imunologia , Linfócitos T/metabolismoRESUMO
OBJECTIVES: NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc. METHODS: Fibrosis was assessed histologically in mice challenged with bleomycin to induce lung or skin fibrosis. RNA sequencing and pathway analysis was performed on wild type and Rel-/- murine lung and dermal fibroblasts. Functional assays examined fibroblast proliferation, migration and matrix production. cRel overexpression was investigated in human dermal fibroblasts. cRel immunostaining was performed on lung and skin tissue sections from SSc patients and non-fibrotic controls. RESULTS: cRel expression was elevated in murine lung and skin fibrosis models. Rel-/- mice were protected from developing pulmonary fibrosis. Soluble collagen production was significantly decreased in fibroblasts lacking cRel while proliferation and migration of these cells was significantly increased. cRel regulates genes involved in extracellular structure and matrix organization. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Overexpression of constitutively active cRel in human dermal fibroblasts increased expression of matrix genes. An NF-κB gene signature was identified in diffuse SSc skin and nuclear cRel expression was elevated in SSc skin fibroblasts. CONCLUSION: cRel regulates a pro-fibrogenic transcriptional programme in fibroblasts that may contribute to disease pathology. Targeting cRel signalling in fibroblasts of SSc patients could provide a novel therapeutic avenue to limit scar formation in this disease.
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Fibroblastos/metabolismo , Proteínas Proto-Oncogênicas c-rel/metabolismo , Escleroderma Sistêmico/metabolismo , Animais , Matriz Extracelular/metabolismo , Fibrose , Imunofluorescência , Regulação da Expressão Gênica , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Escleroderma Sistêmico/patologiaRESUMO
OBJECTIVE: SSc is an autoimmune connective tissue disease that results in skin fibrosis and currently has no effective treatment. Epigenetic modifications have been described and these may be key in initiating and driving fibroblast activation. Among these epigenetic modifications methylation may be of central importance. The aim of this study was to examine the role of methyl cap binding protein-2 (MeCP2) in SSc fibrosis. METHODS: We used healthy and SSc dermal fibroblasts to examine the role of MeCP2, using both small interfering RNA silencing and lentiviral overexpression to determine its effects. We also examined the expression of MeCP2 in SSc fibroblasts by immunoblotting. miRNA132 was quantified by Taqman real time PCR. RESULTS: We demonstrated that TGF-ß1 induced the expression of MeCP2 in normal cells, and showed that SSc fibroblasts expressed high levels of MeCP2 under basal conditions. MeCP2 positively regulated the expression of extracellular matrix through epigenetic repression of the Wnt antagonist sFRP-1, leading to enhanced Wnt signalling. This mediated fibrosis through glycolysis, as the glycolysis inhibitor 2-deoxyglucose diminished the Wnt-mediated collagen expression. MiR132 expression was reduced in SSc fibroblasts. CONCLUSION: The results suggest that an epigenetic loop exists mediating fibrosis. Targeting of MeCP2, as a key epigenetic regulator, may be a promising therapeutic approach, as would targeting the metabolic reprogramming that occurs through aerobic glycolysis.
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Fibroblastos/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , Epigênese Genética , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Células HEK293 , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , RNA Interferente Pequeno , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Pele/efeitos dos fármacos , Pele/patologia , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
The NF-?B p50 subunit is an important regulator of inflammation, with recent experimental evidence to support it also having a tumor suppressor role. Classically, p50 functions in heterodimeric form with the RelA (p65) NF-?B subunit to activate inflammatory genes. However, p50 also forms homodimers which actively repress NF-?B-dependent inflammatory gene expression and exert an important brake on the inflammatory process. This repressive activity of p50:p50 is thought to be in part mediated by an interaction with the epigenetic repressor protein Histone Deacetylase 1 (HDAC1). However, neither the interaction of p50 with HDAC1 nor the requirement of HDAC1 for the repressive activities of p50 has been well defined. Here we employed in silico prediction with in vitro assays to map sites of interaction of HDAC1 on the p50 protein. Directed mutagenesis of one such region resulted in almost complete loss of HDAC1 binding to p50. Transfected mutant p50 protein lacking the putative HDAC1 docking motif resulted in enhanced cytokine and chemokine expression when compared with cells expressing a transfected wild type p50. In addition, expression of this mutant p50 was associated with enhanced chemoattraction of neutrophils and acetylation of known inflammatory genes demonstrating the likely importance of the p50:HDAC1 interaction for controlling inflammation. These new insights provide an advance on current knowledge of the mechanisms by which NF-?B-dependent gene transcription are regulated and highlight the potential for manipulation of p50:HDAC1 interactions to bring about experimental modulation of chronic inflammation and pathologies associated with dysregulated neutrophil accumulation and activation.
Assuntos
Histona Desacetilase 1/metabolismo , Subunidade p50 de NF-kappa B/química , Subunidade p50 de NF-kappa B/metabolismo , Animais , Linhagem Celular , Quimiocinas/genética , Quimiotaxia , Montagem e Desmontagem da Cromatina , Expressão Gênica , Histona Desacetilase 1/química , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Subunidade p50 de NF-kappa B/genética , Neutrófilos/imunologia , Sinais de Localização NuclearRESUMO
Idiopathic pulmonary fibrosis (IPF), a chronic progressive interstitial pneumonia, is characterized by excessive fibroproliferation. Key effector cells in IPF are myofibroblasts that are recruited from three potential sources: resident fibroblasts, fibrocytes, and epithelial cells. We hypothesized that IPF myofibroblasts from different sources display unique gene expression differences and distinct functional characteristics. Primary human pulmonary fibroblasts (normal and IPF), fibrocytes, and epithelial cells were activated using the profibrotic factors TGF-ß and TNF-α. The resulting myofibroblasts were characterized using cell proliferation, soluble collagen, and contractility assays, ELISA, and human fibrosis PCR arrays. Genes of significance in human whole lung were validated by immunohistochemistry on human lung sections. Fibroblast-derived myofibroblasts exhibited the greatest increase in expression of profibrotic genes and genes involved in extracellular matrix remodeling and signal transduction. Functional studies demonstrated that myofibroblasts derived from fibrocytes expressed mostly soluble collagen and chemokine (C-C) motif ligand (CCL) 18 but were the least proliferative of the myofibroblast progeny. Activated IPF fibroblasts displayed the highest levels of contractility and CCL2 production. This study identified novel differences in gene expression and functional characteristics of different myofibroblast populations. Further investigation into the myofibroblast phenotype may lead to potential therapeutic targets in future IPF research.
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Fibroblastos/patologia , Regulação da Expressão Gênica , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Miofibroblastos/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Miofibroblastos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoRESUMO
Epithelial to mesenchymal cell transition (EMT), whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). CXCR3 and its ligands are recognized to play a protective role in pulmonary fibrosis. In this study, we investigated the presence and extent of EMT and CXCR3 expression in human IPF surgical lung biopsies and assessed whether CXCR3 and its ligand CXCL9 modulate EMT in alveolar epithelial cells. Coexpression of the epithelial marker thyroid transcription factor-1 and the mesenchymal marker α-smooth muscle actin and CXCR3 expression was examined by immunohistochemical staining of IPF surgical lung biopsies. Epithelial and mesenchymal marker expression was examined by quantitative real-time PCR, Western blotting, and immunofluorescence in human alveolar epithelial (A549) cells treated with TGF-ß1 and CXCL9, with Smad2, Smad3, and Smad7 expression and cellular localization examined by Western blotting. We found that significantly more cells were undergoing EMT in fibrotic versus normal areas of lung in IPF surgical lung biopsy samples. CXCR3 was expressed by type II pneumocytes and fibroblasts in fibrotic areas in close proximity to cells undergoing EMT. In vitro, CXCL9 abrogated TGF-ß1-induced EMT. A decrease in TGF-ß1-induced phosphorylation of Smad2 and Smad3 occurred with CXCL9 treatment. This was associated with increased shuttling of Smad7 from the nucleus to the cytoplasm where it inhibits Smad phosphorylation. This suggests a role for EMT in the pathogenesis of IPF and provides a novel mechanism for the inhibitory effects of CXCL9 on TGF-ß1-induced EMT.
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Quimiocina CXCL9/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Fibrose Pulmonar Idiopática/patologia , Mucosa Respiratória/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Actinas/biossíntese , Biomarcadores/metabolismo , Linhagem Celular , Quimiocina CXCL9/farmacologia , Células Epiteliais/metabolismo , Humanos , Proteínas Nucleares/biossíntese , Fosforilação , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/metabolismo , Receptores CXCR3/biossíntese , Receptores CXCR3/metabolismo , Mucosa Respiratória/citologia , Proteína Smad2/biossíntese , Proteína Smad3/biossíntese , Proteína Smad7/biossíntese , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/biossíntese , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
Pulmonary fibrosis is a progressive and fatal disease that involves the remodeling of the distal airspace and the lung parenchyma, which results in compromised gas exchange. The median survival time once diagnosed is less than three years. Interleukin (IL)-13 has been shown to play a role in a number of inflammatory and fibrotic diseases. IL-13 modulates its effector functions via a complex receptor system that includes the IL-4 receptor (R) α, IL-13Rα1, and the IL-13Rα2. IL-13Rα1 binds IL-13 with low affinity, yet, when it forms a complex with IL-4α, it binds with much higher affinity, inducing the effector functions of IL-13. IL-13Rα2 binds IL-13 with high affinity but has a short cytoplasmic tail and has been shown to act as a nonsignaling decoy receptor. Transfection of fibroblasts and epithelial cells with IL-13Rα2 inhibited the IL-13 induction of soluble collagen, TGF-ß, and CCL17. Adenoviral overexpression of IL-13Rα2 in the lung reduced bleomycin-induced fibrosis. Our work shows that overexpression of IL-13Rα2 inhibits the IL-13 induction of fibrotic markers in vitro and inhibits bleomycin-induced pulmonary fibrosis. In summary our study highlights the antifibrotic nature of IL-13Ra2.
Assuntos
Subunidade alfa2 de Receptor de Interleucina-13/fisiologia , Fibrose Pulmonar/metabolismo , Animais , Bleomicina , Quimiocina CCL17/biossíntese , Colágeno/biossíntese , Células HEK293 , Humanos , Interleucina-13/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Fibrose Pulmonar/induzido quimicamente , Fator de Crescimento Transformador beta/biossínteseRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibrosis and abnormal vascularity. IL-13, a profibrotic cytokine that plays a role in IPF, functions through the Jak/STAT pathway after binding to the IL-13 receptor α1 (IL-13Rα1)/IL-4Rα complex. IL-13 also binds to IL-13Rα2, which has been thought to function as a nonsignaling decoy receptor, although possible signaling roles of this receptor have been proposed. CXCR3 and its IFN-inducible ligands-CXCL9, CXCL10, and CXCL11-have been implicated in vascular remodeling and fibroblast motility during the development of IPF. In this study, CXCR3 expression was demonstrated in cultured pulmonary fibroblasts from wild-type BALB/c mice and was found to be necessary for the IL-13-mediated gene and protein up-regulation of IL-13Rα2. In fibroblasts from CXCR3-deficient mice, STAT6 activation was prolonged. This study is the first to demonstrate the expression of CXCR3 in fibroblasts and its association with the expression of IL-13Rα2. Taken together, the results from this study point strongly to a requirement for CXCR3 for IL-13-mediated IL-13Rα2 gene expression. Understanding the function of CXCR3 in IL-13-mediated lung injury may lead to novel approaches to combat the development of pulmonary fibrosis, whether by limiting the effects of IL-13 or by manipulation of angiostatic pathways. The elucidation of the complex relationship between these antifibrotic receptors and manipulation of the CXCR3-mediated regulation of IL-13Rα2 may represent a novel therapeutic modality in cases of acute lung injury or chronic inflammation that may progress to fibrosis.