Distinct Roles of Hepatocyte- and Myeloid Cell-Derived IL-1 Receptor Antagonist during Endotoxemia and Sterile Inflammation in Mice

Lamacchia, Céline; Palmer, Gaby; Bischoff, Loraine; Rodriguez, Emiliana; Talabot-Ayer, Dominique; Gabay, Cem

doi:10.4049/jimmunol.1000872

Cited by 21 publications

(24 citation statements)

References 40 publications

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“…Thus, transferred B cells may indeed modulate the functions of innate immune cells in lung and spleen to also promote regulatory dendritic cells or macrophages capable of producing IL-10 and other innate immune regulators (reviewed in references 85 and 86). This finding would be consistent with the concomitant upregulation of IL-10, IL-27, and also IL1Ra observed in B cell-transferred IFrag Ϫ/Ϫ mice (80,87,88). In support of this, we found in preliminary experiments that coculture of B cells with pulmonary CD11b…”

Section: Discussionsupporting

confidence: 88%

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

et al. 2015

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HIV infection results in a complex immunodeficiency due to loss of CD4؉ T cells, impaired type I interferon (IFN) responses, and B cell dysfunctions causing susceptibility to opportunistic infections such as Pneumocystis murina pneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity to Pneumocystis lung infection. We recently also identified B cells as supporters of on-demand hematopoiesis following Pneumocystis infection that would otherwise be hampered due to systemic immune effects initiated in the context of a defective type I IFN system. While studying the role of type I IFNs in immunity to Pneumocystis infection, we discovered that mice lacking both lymphocytes and type I IFN receptor (IFrag Pneumocystis is a ubiquitous extracellular pulmonary fungal pathogen with strict species specificity. It is likely contracted via airborne transmission from often transiently infected individuals and commonly causes few or unspecific symptoms in otherwise healthy individuals leading to immunity (reviewed in references 1 and 2). However, Pneumocystis can cause severe and progressive interstitial pneumonia in patients with impaired acquired immunity with mortality rates up to 60% (3). While the total number of functional CD4 ϩ T cells critically determines increased susceptibility to Pneumocystis lung infection, patients with B cell defects are also at risk. In this regard, Pneumocystis pneumonia (PCP) is an AIDSdefining condition during HIV disease progression and commonly occurs when CD4 ϩ T cell counts drop below 200 cells/l (4). Furthermore, immune suppressive and cell ablative therapy following solid-organ transplantation, autoimmunity, or cancer treatment reduce CD4 ϩ T cell and/or B cell numbers and impair functions in non-HIV patients (reviewed in references 5 and 6). Drug regimens that predispose to severe Pneumocystis infections include high-dose glucocorticoid and B cell ablative treatments with rituximab (7-11). In addition, low-grade Pneumocystis infection is found in patients with potentially subtle immune suppressions such as young infants, HIV-positive patients receiving HAART (highly active antiretroviral therapy), or patients receiving low-dose and inhaled glucocorticoids (12)(13)(14). This can promote bronchial hyperreactivity, is associated with sudden infant death syndrome (SIDS) and exacerbation of chronic obstructive lung diseases (15)(16)(17)(18)(19).Pneumocystis colonization also intensifies signs of systemic inflammation (20, 21). Thus, Pneumocystis may act as a profound comorbidity factor that may also enhance secondary systemic disease manifestations associated with chronic pulmonary diseases and HIV infection such as osteoporosis or bone marrow dysfunctions (22-28). Immunity to Pneumocystis requires the presence of functional CD4 ϩ T cells to stimulate antigen-specific immune globulin production by B cells and macrophage-mediated phagocytosis (4,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). In addition, early innate t...

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Section: Discussionsupporting

confidence: 88%

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

et al. 2015

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“…qualitative difference between IL-1Ra and IL-1R2. The finding that IL-1R2 plays a marginal role, if any, in the control of systemic responses to acute administration of IL-1 or LPS, whereas IL-1Ra plays a crucial role in these two inflammatory situations (28,29), emphasizes the difference between these two IL-1 inhibitors. Even though neutrophils are recruited from the bone marrow to the circulation in systemic responses, a concentration of neutrophils and IL-1R2 as high as that locally reached in arthritic joints is not achieved, suggesting a predominantly local regulatory function of IL-1R2.…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that IL-1Ra, another regulator of IL-1 bioactivity, plays a critical role during IL-1b-induced sterile inflammation (28) and lethal endotoxemia (28,29). The assessment of serum levels of IL-6, CXCL1, and CXCL2 as markers for inflammation at different time points upon administration of two doses of IL-1b at 0 and 12 h showed no difference between IL-1R2 2/2 and WT mice, except for significantly higher IL-6 levels in serum of IL-1R2 2/2 compared with WT mice 36 h after the first IL-1b injection (Fig.…”

Section: No Effect Of Il-1r2 Deficiency On Il-1b-induced Sterile Inflmentioning

confidence: 99%

Deficiency in IL-1 Receptor Type 2 Aggravates K/BxN Serum Transfer-Induced Arthritis in Mice but Has No Impact on Systemic Inflammatory Responses

Martin

Palmer

Rodriguez

et al. 2017

The Journal of Immunology

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The biological activity of IL-1 is tightly regulated by the specific receptor antagonist (IL-1Ra) and the decoy receptor IL-1 receptor type 2 (IL-1R2). The role of IL-1Ra has been well demonstrated in IL-1Ra–deficient mice. In contrast, the role of endogenous IL-1R2 remains widely unknown. To define the functional role of endogenous IL-1R2 in the K/BxN serum transfer arthritis model and in IL-1β– or LPS-induced systemic inflammation in vivo, IL-1R2−/− mice were created and compared with wild type mice. IL-1R2−/− mice bred habitually and exhibited a normal phenotype. IL-1R2 deficiency aggravated arthritis severity and increased mRNA levels for key cytokines and chemokines such as IL-6, IL-1β, Cxcl-1, and Cxcl-2 significantly in ankles. There was no effect of IL-1R2 deficiency on the cell-autonomous cytokine response to IL-1β in the tested cell types, i.e., neutrophils, macrophages, and fibroblasts, but IL-1R2 deficiency on neutrophils increased the IL-1–induced response of fibroblasts in trans. Furthermore, IL-1β induced shedding of IL-1R2 in vivo. Inflammatory responses to IL-1β and LPS-induced mortality were not different in IL-1R2−/− compared with wild type mice. Our data demonstrate that the decoy receptor IL-1R2 plays an important inhibitory role in local IL-1– and neutrophil-dependent tissue inflammation as shown in the K/BxN serum transfer arthritis model. In contrast to IL-1Ra, IL-1R2 appears to be less crucial for systemic responses to acute administration of IL-1 or LPS.

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“…However, treatment with recombinant IL1RN (anakinra) has been shown to be antidiabetic, improving both insulin sensitivity and beta cell function (38,39), suggesting that the increase in IL1RN may represent a compensatory change to proinflammatory signals. The liver is a major source of circulating ILRN (40). PGC-1␣ is induced in liver by caloric restriction and exercise (both conditions improving insulin sensitivity and glucose tolerance (41)).…”

Section: Discussionmentioning

confidence: 99%

Energy-sensing Factors Coactivator Peroxisome Proliferator-activated Receptor γ Coactivator 1-α (PGC-1α) and AMP-activated Protein Kinase Control Expression of Inflammatory Mediators in Liver

Buler

Aatsinki

Skoumal

et al. 2012

Journal of Biological Chemistry

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Background: Metabolic disorders are associated with chronic inflammation. Results: Energy-sensing factor PGC-1␣ regulates cytokine expression in hepatocytes. PGC-1␣, AMPK, and metformin induce expression of interleukin 1 receptor antagonist. Conclusion: PGC-1␣ and AMPK mediate effects of fasting, physical exercise, and antidiabetic drug metformin on hepatic inflammatory gene expression. Significance: PGC-1␣ and AMPK are regulatory interlinks between energy homeostasis and inflammation.

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Distinct Roles of Hepatocyte- and Myeloid Cell-Derived IL-1 Receptor Antagonist during Endotoxemia and Sterile Inflammation in Mice

Abstract: Material Supplementary 2.DC1http://www.jimmunol.org/content/suppl/2010/07/16/jimmunol.100087

Cited by 21 publications

References 40 publications

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

Deficiency in IL-1 Receptor Type 2 Aggravates K/BxN Serum Transfer-Induced Arthritis in Mice but Has No Impact on Systemic Inflammatory Responses

Energy-sensing Factors Coactivator Peroxisome Proliferator-activated Receptor γ Coactivator 1-α (PGC-1α) and AMP-activated Protein Kinase Control Expression of Inflammatory Mediators in Liver

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