Regulator of Calcineurin 1 (Rcan1) Is Required for the Development of Pulmonary Eosinophilia in Allergic Inflammation in Mice

Yang, Yong; MacNeil, Adam J.; Junkins, Robert D.; Carrigan, Svetlana O.; Tang, Jintian; Forward, Nicholas; Berman, Jason N.; Lin, Tong‐Jun

doi:10.1016/j.ajpath.2011.05.022

Cited by 14 publications

(13 citation statements)

References 49 publications

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“…GM-CSF promoted increases in GMPs and downstream EoPs, which both express GM-CSF-R-α and β chains ( Iwasaki et al., 2005 ). Increased EoPs have been observed in Th2 cell-mediated asthma and anti-helminth responses ( Iwasaki et al., 2005; Yang et al., 2011 ), however, our study constitutes the first report of chronic EoP accumulation during IL-23-Th17 cell type-mediated immune disease, extending our previous observation of dysregulated hematopoiesis in colitis to the eosinophilic lineage.…”

Section: Discussionsupporting

confidence: 68%

Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis

et al. 2015

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SummaryThe role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target.

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Section: Discussionsupporting

confidence: 68%

Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis

et al. 2015

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“…MPO was estimated as described elsewhere (Yang et al ., ). Briefly, equal volumes (75 μL) of samples and substrate (3 mM 3,3′,5,5′‐tetramethylbenzidine dihydrochloride, 120 μmol L −1 resorcinol and 2.2 mmol L −1 H 2 O 2 ) were mixed and incubated at room temperature for 2 min.…”

Section: Methodsmentioning

confidence: 97%

The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL‐4 and IL‐10

Jain

Woodruff

Stadnyk

2012

British J Pharmacology

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BACKGROUND AND PURPOSEAnti-complement therapies have not been advanced for treating the inflammatory bowel diseases (IBDs) despite a growing body of evidence that blocking C5a protects against induced colitis in rodents. The purpose of this study was to further build on this evidence by examining the efficacy, mechanism and specificity of a potent, non-competitive and orally active C5a receptor (CD88) antagonist, PMX205, in the dextran sulphate sodium (DSS) model of murine innate colitis. EXPERIMENTAL APPROACHMice with DSS added to their drinking water were orally administered 100 or 200 mg day -1 PMX205 in prophylactic and therapeutic regimens. Clinical illness, colon histology and local generation of inflammatory mediators were measured to evaluate the impact of PMX205 on disease. KEY RESULTSPMX205 significantly prevented DSS-induced colon inflammation in both regimens, associated with lower pro-inflammatory cytokine production and nitrotyrosine staining in colon sections. Additionally, the levels of anti-inflammatory cytokines IL-4 and IL-10 were increased. PMX205 had no significant effect on C5a levels. The beneficial effect of PMX205 was seen in two strains of mice of differing sensitivities to DSS inflammation, but was inactive in mice lacking CD88. CONCLUSIONS AND IMPLICATIONSPharmacological inhibition of C5a activity by PMX205 is efficacious in preventing DSS-induced colitis, providing further evidence that targeting CD88 in IBD patients could be a valuable therapeutic option.

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“…Intriguingly, previous studies have proposed RCAN1 as both an inhibitor (67)(68)(69)(70) and an activator (19,23,(71)(72)(73) of inflammation via calcineurin, suggesting that the biological activity of the protein might be context dependent. To our knowledge, our findings in this work provide the first evidence of a negative regulatory role for RCAN1 in inflammation during respiratory tract infections using an in vivo model of bacterial pneumonia.…”

Section: Discussionmentioning

confidence: 99%

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Junkins

MacNeil

et al. 2013

The Journal of Immunology

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Respiratory tract infection with Pseudomonas aeruginosa is a common cause of hospitalization in immune-compromised individuals. However, the molecular mechanisms involved in the immune response to P. aeruginosa lung infection remain incompletely defined. In this study, we demonstrate that the regulator of calcineurin 1 (RCAN1) is a central negative regulator of inflammation in a mouse model of acute bacterial pneumonia using the opportunistic bacterial pathogen P. aeruginosa. RCAN1-deficient mice display greatly increased mortality following P. aeruginosa lung infection despite enhanced neutrophil recruitment and bacterial clearance. This mortality is associated with higher systemic levels of proinflammatory cytokines in RCAN1-deficient animals. These aberrant inflammatory responses coincide with increased transcriptional activity of proinflammatory RCAN1-target proteins NFAT and NF-κB. In addition, we reveal a novel regulatory role for RCAN1 in the ERK/STAT3 pathway both in vitro and in vivo, suggesting that aberrant STAT3 activity may significantly contribute to delayed resolution of inflammatory responses in our model. Together, these findings demonstrate that RCAN1 is a potent negative regulator of inflammation during respiratory tract infections.

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Regulator of Calcineurin 1 (Rcan1) Is Required for the Development of Pulmonary Eosinophilia in Allergic Inflammation in Mice

Cited by 14 publications

References 49 publications

Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis

Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis

The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL‐4 and IL‐10

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

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