Regnase-1 is essential for B cell homeostasis to prevent immunopathology

Bhat, Numana; Virgen-Slane, Richard; Ramezani-Rad, Parham; Leung, Charlotte R; Chen, Cindi; Balsells, Daniel; Shukla, Ashima; Kao, Elaine; Apgar, John R.; Fu, Mingui; Ware, Carl F.; Rickert, Robert C.

doi:10.1084/jem.20200971

Cited by 17 publications

(11 citation statements)

References 51 publications

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“…3B and C ). It is known that Reg1 controls B cell homeostasis and that complete Reg1 deletion in B cells increases antibody secretion ( 26 ). However, IgM and IgA levels in BALF and lung tissue were comparable between Reg1 +/− and control mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Regnase-1 Deficiency Restrains Klebsiella pneumoniae Infection by Regulation of a Type I Interferon Response

Trevejo-Nuñez

Lin

Fan

et al. 2022

mBio

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Section: Resultsmentioning

confidence: 99%

Regnase-1 Deficiency Restrains Klebsiella pneumoniae Infection by Regulation of a Type I Interferon Response

Trevejo-Nuñez

Lin

Fan

et al. 2022

mBio

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“…Molecules functionally important in ABC expansion or function were also significantly affected. ZC3H12A , which encodes the RNA-binding protein REGNASE-1, was decreased in Cluster 1 ( Figure 5D,E ), and Regnase-1 deficiency at earlier stages of B cell development in mice produces severe autoimmune immunopathology and early mortality, accompanied by ABC expansion ( 67 ). TBX21 (encoding TBET ), ZEB2 and EGR3 are important and potential master regulators of ABC development and/or function in mice and humans ( 18, 20, 21, 59 ), and each were Up DEGs in either ‘memory’ Cluster 5 ( TBX21 , ZEB2 ) or activated Cluster 9 ( EGR3 ), Figure 5C,E .…”

Section: Resultsmentioning

confidence: 99%

“…ZC3H12A, which encodes the RNA-binding protein REGNASE-1, was decreased in Cluster 1 (Fig. 5D,E), and Regnase-1 deficiency at earlier stages of B cell development in mice produces severe autoimmune immunopathology and early mortality, accompanied by ABC expansion (80).…”

Section: Genes Critical For B Cell Fate and Function Are Differential...mentioning

confidence: 97%

Single-cell Landscape Analysis Unravels Molecular Programming of the Human B Cell Compartment in Chronic GVHD

Poe

Fang

Zhang

et al. 2022

Preprint

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After allogeneic hematopoietic stem cell transplantation (allo-HCT), donor-derived B cells develop under selective pressure from alloantigens and play a substantiated role in the autoimmune-like syndrome, chronic graft versus host disease (cGVHD). We performed single-cell RNA-Sequencing (scRNA-Seq) of blood B cells from allo-HCT patients and resolved 10 clusters that were distinguishable by signature genes for maturation, activation and memory. Notably, allo-HCT patient memory B cells displayed some striking transcriptional differences when compared to memory B cells from healthy individuals or non-HCT patients, suggesting molecular differences with a propensity for autoreactivity. To inform more specifically about transcriptional programs important for allo-HCT tolerance, we assessed all 10 clusters for differentially expressed genes (DEGs) between patients with Active cGVHD vs. those without disease (No cGVHD). Data reveal insight into DEGs that may influence multiple aspects of B cell function in allo-HCT, leading to chronic B cell activation in Active cGVHD and our observed expansion of potentially pathogenic atypical/age-related memory B cell (ABC) subsets within a B Cell Receptor (BCR)-experienced memory cluster. Data also indicate chronic B-cell activation and diversification in allo-HCT is potentially plastic, and may be manipulated therapeutically. Our findings have implications in understanding how alloreactivity may lead to human autoimmune disease, and identify potentially novel targets for future study and intervention.

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“…There were also no differences in cellular proliferation and macrophage bacterial killing between Reg1 +/− and control mice ( Fig 3B, C ). It is known that Reg1 controls B cell homeostasis and that complete Reg1 deletion in B cells increases antibody secretion (28). However, IgM and IgA levels in BALF and lung tissue were comparable between Reg1 +/− and control mice ( Fig 3D ).…”

Section: Resultsmentioning

confidence: 99%

Regnase-1 deficiency restrains Klebsiella pneumoniae infection by regulation of a Type I interferon response

Trevejo-Nuñez

Fan

Lin

et al. 2021

Preprint

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Excessive inflammatory responses can cause collateral tissue damage or autoimmune inflammation, sometimes with severe morbidity or mortality. During host defense responses, numerous negative feedback mechanisms are established to prevent excessive unchecked inflammation. However, this restraint can sometimes come at the cost of suboptimal infection control, and we do not fully understand how this balance is maintained during different infection settings. The endoribonuclease Regnase-1 (Reg1, Zc3h12a, MCPIP1) is an RNA binding protein (RBP) that binds and degrades many target mRNA transcripts. Reg1 is a potent feedback regulator of IL-17 and LPS signal transduction, among other stimuli. Consequently, Reg1 deficiency exacerbates autoimmune inflammation in multiple mouse models, but on the other hand, reduced Reg1 improves immunity to fungal infection. To date, the role of Reg1 in bacterial immunity is poorly defined. Here, we show that mice deficient in Reg1 are more resistant to pulmonary Klebsiella pneumoniae (KP) infection. Unexpectedly, effects of Reg1 deficiency were not due to accelerated eradication of bacteria or increased pro-inflammatory cytokine expression. Rather, alveolar macrophages from Reg1-deficient mice showed enrichment of Type I IFN-related genes upon KP infection, accompanied by increased Ifnb1 expression. Surprisingly, the stability of Ifnb1 was not altered by Reg1-deficiency; rather, mRNA encoding its upstream regulator IRF7 appeared to be a more prominent target. Thus, impaired Reg1 induces Type I IFN and enhances resistance to KP, raising the possibility that Reg1 could be a potential clinical target in acute bacterial infections.Graphical abstract

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Regnase-1 is essential for B cell homeostasis to prevent immunopathology

Cited by 17 publications

References 51 publications

Regnase-1 Deficiency Restrains Klebsiella pneumoniae Infection by Regulation of a Type I Interferon Response

Regnase-1 Deficiency Restrains Klebsiella pneumoniae Infection by Regulation of a Type I Interferon Response

Single-cell Landscape Analysis Unravels Molecular Programming of the Human B Cell Compartment in Chronic GVHD

Regnase-1 deficiency restrains Klebsiella pneumoniae infection by regulation of a Type I interferon response

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