scholarly journals LRRK2 plays essential roles in maintaining lung homeostasis and preventing the development of pulmonary fibrosis

2021 ◽  
Vol 118 (35) ◽  
pp. e2106685118
Author(s):  
Yujie Tian ◽  
Jiaoyan Lv ◽  
Ziyan Su ◽  
Tao Wu ◽  
Xiaoguang Li ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Immune Responses ◽  
Respiratory Diseases ◽  
Innate Immune ◽  
Alveolar Type ◽  
Type Ii ◽  
Innate Immune Responses ◽  
Leucine Rich Repeat ◽  
Cell Dysfunction ◽  
Deficient Mice

Perturbation of lung homeostasis is frequently associated with progressive and fatal respiratory diseases, such as pulmonary fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in healthy lungs, but its functions in lung homeostasis and diseases remain elusive. Herein, we showed that LRRK2 expression was clearly reduced in mammalian fibrotic lungs, and LRRK2-deficient mice exhibited aggravated bleomycin-induced pulmonary fibrosis. Furthermore, we demonstrated that in bleomycin-treated mice, LRRK2 expression was dramatically decreased in alveolar type II epithelial (AT2) cells, and its deficiency resulted in profound dysfunction of AT2 cells, characterized by impaired autophagy and accelerated cellular senescence. Additionally, LRRK2-deficient AT2 cells showed a higher capacity of recruiting profibrotic macrophages via the CCL2/CCR2 signaling, leading to extensive macrophage-associated profibrotic responses and progressive pulmonary fibrosis. Taken together, our study demonstrates that LRRK2 plays a crucial role in preventing AT2 cell dysfunction and orchestrating the innate immune responses to protect against pulmonary fibrosis.

CCRI-DEFICIENT MICE SHOW ENHANCED INNATE IMMUNE RESPONSES AND ARE PROTECTED IN A CLP MODEL OF SEPSIS

Shock ◽  
2004 ◽  
Vol 21 (Supplement) ◽  
pp. 69
Author(s):  
T. L. Ness ◽  
K. J. Carpenter ◽  
J. L. Ewing ◽  
C. M. Hogaboam ◽  
S L Kunkel
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Deficient Mice

scholarly journals Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Bin Zhou ◽  
Fei Qi ◽  
Fangyi Wu ◽  
Hongbo Nie ◽  
Yifan Song ◽  
...  
Keyword(s):  
Immune Responses ◽  
Transcriptome Analysis ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Innate Immune ◽  
Endogenous Retroviruses ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Positive Regulator ◽  
Deficient Mice

ABSTRACT Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this “enemy within” may encode a viral mimic to induce antiviral immune responses through viral sensors. Here, through whole-genome transcriptome analysis with RNA sequencing (RNA-Seq), we discovered that a full-length ERV-derived long noncoding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), was a positive regulator of NF-κB signaling. lnc-EPAV expression was rapidly upregulated by viral RNA mimics or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a crucial role in antiviral responses. Transcriptome analysis of lnc-EPAV-silenced macrophages showed that lnc-EPAV was critical for RELA target gene expression and innate immune responses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I interferons (IFNs) and, consequently, increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of Rela. Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses. IMPORTANCE Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control Rela transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.

scholarly journals IL-17A in Human Respiratory Diseases: Innate or Adaptive Immunity? Clinical Implications

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Dominique M. A. Bullens ◽  
Ann Decraene ◽  
Sven Seys ◽  
Lieven J. Dupont
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Respiratory Diseases ◽  
Inflammatory Diseases ◽  
Cell Lineage ◽  
Innate Immune ◽  
Clinical Implications ◽  
Innate Immune Cells ◽  
Innate Immune Responses

Since the discovery of IL-17 in 1995 as a T-cell cytokine, inducing IL-6 and IL-8 production by fibroblasts, and the report of a separate T-cell lineage producing IL-17(A), called Th17 cells, in 2005, the role of IL-17 has been studied in several inflammatory diseases. By inducing IL-8 production and subsequent neutrophil attraction towards the site of inflammation, IL-17A can link adaptive and innate immune responses. More specifically, its role in respiratory diseases has intensively been investigated. We here review its role in human respiratory diseases and try to unravel the question whether IL-17A only provides a link between the adaptive and innate respiratory immunity or whether this cytokine might also be locally produced by innate immune cells. We furthermore briefly discuss the possibility to reduce local IL-17A production as a treatment option for respiratory diseases.

scholarly journals Keratinocyte growth factor supports pulmonary innate immune defense through maintenance of alveolar antimicrobial protein levels and macrophage function

2016 ◽  
Vol 310 (9) ◽  
pp. L868-L879 ◽  
Author(s):  
Jason C. Gardner ◽  
Huixing Wu ◽  
John G. Noel ◽  
Benjamin J. Ramser ◽  
Lori Pitstick ◽  
...  
Keyword(s):  
Keratinocyte Growth Factor ◽  
Surfactant Protein ◽  
Immune Defense ◽  
Innate Immune ◽  
Antimicrobial Protein ◽  
Alveolar Type ◽  
Type Ii ◽  
Protein Levels ◽  
Innate Immune Defense ◽  
Deficient Mice

Keratinocyte growth factor (KGF) is an epithelial mitogen that has been reported to protect the lungs from a variety of toxic and infectious insults. In prior studies we found that recombinant human KGF accelerates clearance of bacteria from the murine lung by augmenting the function of alveolar macrophages (AM). In this study we tested the hypothesis that endogenous KGF plays a role in the maintenance of innate pulmonary defense against gram-negative bacterial infections. KGF-deficient mice exhibited delayed clearance of Escherichia coli from the lungs, attenuated phagocytosis by AM, and decreased antimicrobial activity in bronchoalveolar lavage (BAL) fluid, due in part to reductions in levels of surfactant protein A, surfactant protein D, and lysozyme. These immune deficits were accompanied by lower alveolar type II epithelial cell counts and reduced alveolar type II epithelial cell expression of collectin and lysozyme genes on a per cell basis. No significant between-group differences were detected in selected inflammatory cytokines or BAL inflammatory cell populations at baseline or after bacterial challenge in the wild-type and KGF-deficient mice. A single intranasal dose of recombinant human KGF reversed defects in bacterial clearance, AM function, and BAL fluid antimicrobial activity. We conclude that KGF supports alveolar innate immune defense through maintenance of alveolar antimicrobial protein levels and functions of AM. Together these data demonstrate a role for endogenous KGF in maintenance of normal pulmonary innate immune function.

scholarly journals B cells enhance early innate immune responses during bacterial sepsis

2011 ◽  
Vol 208 (8) ◽  
pp. 1673-1682 ◽  
Author(s):  
Kindra M. Kelly-Scumpia ◽  
Philip O. Scumpia ◽  
Jason S. Weinstein ◽  
Matthew J. Delano ◽  
Alex G. Cuenca ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Bacterial Sepsis ◽  
Sepsis Survival ◽  
Deficient Mice

Microbes activate pattern recognition receptors to initiate adaptive immunity. T cells affect early innate inflammatory responses to viral infection, but both activation and suppression have been demonstrated. We identify a novel role for B cells in the early innate immune response during bacterial sepsis. We demonstrate that Rag1−/− mice display deficient early inflammatory responses and reduced survival during sepsis. Interestingly, B cell–deficient or anti-CD20 B cell–depleted mice, but not α/β T cell–deficient mice, display decreased inflammatory cytokine and chemokine production and reduced survival after sepsis. Both treatment of B cell–deficient mice with serum from wild-type (WT) mice and repletion of Rag1−/− mice with B cells improves sepsis survival, suggesting antibody-independent and antibody-dependent roles for B cells in the outcome to sepsis. During sepsis, marginal zone and follicular B cells are activated through type I interferon (IFN-I) receptor (IFN-α/β receptor [IFNAR]), and repleting Rag1−/− mice with WT, but not IFNAR−/−, B cells improves IFN-I–dependent and –independent early cytokine responses. Repleting B cell–deficient mice with the IFN-I–dependent chemokine, CXCL10 was also sufficient to improve sepsis survival. This study identifies a novel role for IFN-I–activated B cells in protective early innate immune responses during bacterial sepsis.

scholarly journals SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial derived cells and cardiomyocytes

2020 ◽  
Author(s):  
Yize Li ◽  
David M Renner ◽  
Courtney E Comar ◽  
Jillian N Whelan ◽  
Hanako M Reyes ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Immune Responses ◽  
Innate Immune ◽  
Alveolar Type ◽  
Rnase L ◽  
Innate Immune Responses ◽  
Oligoadenylate Synthetase ◽  
Protein Kinase R ◽  
Double Stranded Rna ◽  
Ribonuclease L

SummaryCoronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase–ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection, induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung, and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, while PKR activation is evident in iAT2 and iCM. In SARS-CoV-2 infected Calu-3 and A549ACE2 lung-derived cell lines, IFN induction remains relatively weak; however activation of OAS-RNase L and PKR is observed. This is in contrast to MERS-CoV, which effectively inhibits IFN signaling as well as OAS-RNase L and PKR pathways, but similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, both OAS-RNase L and PKR are activated in MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.SignificanceSARS-CoV-2 emergence in late 2019 led to the COVID-19 pandemic that has had devastating effects on human health and the economy. Early innate immune responses are essential for protection against virus invasion. While inadequate innate immune responses are associated with severe COVID-19 diseases, understanding of the interaction of SARS-CoV-2 with host antiviral pathways is minimal. We have characterized the innate immune response to SARS-CoV-2 infections in relevant respiratory tract derived cells and cardiomyocytes and found that SARS-CoV-2 activates two antiviral pathways, oligoadenylate synthetase–ribonuclease L (OAS-RNase L), and protein kinase R (PKR), while inducing minimal levels of interferon. This in contrast to MERS-CoV which inhibits all three pathways. Activation of these pathways may contribute to the distinctive pathogenesis of SARS-CoV-2.

ISG12 Is a Critical Modulator of Innate Immune Responses in Animal Models of Septis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1274-1274
Author(s):  
Gernot Schabbauer ◽  
Nikolina Papac-Milicevic ◽  
Pavel Uhrin ◽  
Bernd Binder
Keyword(s):  
Immune Responses ◽  
Nuclear Receptors ◽  
Nuclear Export ◽  
Innate Immune ◽  
Experimental Sepsis ◽  
Innate Immune Responses ◽  
Anti Inflammatory ◽  
Deficient Mice

Abstract Sepsis is still a major burden for the society with a high incidence of morbidity and mortality each year. Molecular mechanisms underlying the systemic inflammatory response syndrome (SIRS) associated with sepsis are still ill defined and most therapies developed to target the acute inflammatory component of the disease are insufficent. Recently the role of nuclear receptors (NRs) in transcriptional regulation of inflammatory processes became a major topic of interest. Nuclear receptors, such as the peroxisome proliferators-activated receptors (PPARs), have been found to exert anti-inflammatory properties by interfering with the NFkB pathway. We are interested in the nuclear envelope protein, interferon stimulated gene 12 (ISG12), which directly interacts with NRs. ISG12 is a co-factor stimulating nuclear export of NRs, thereby reducing the anti-inflammatory potential of NRs such as PPARg or NR4A1. To examine the role of ISG12 in acute inflammation we generated ISG12 deficient mice. We can demonstrate by reverse genetics in ISG12 deficient mice that lack of ISG12 is beneficial in experimental sepsis and endotoxemia. Furthermore we can show that several acute inflammatory parameters, such as systemic IL6 cytokine levels, are downregulated in septic ISG12-/- animals. Consistently, similar results could be obtained in in vitro experiments in peritoneal macrophages derived from ISG12 deficient mice. In contrast, mice deficient for the nuclear receptor NR4A1 exhibited an exacerbated innate immune response and showed a significantly higher mortality after lethal septic challenge. This dramatic phenotype could be restored in ISG12/NR4A1 double deficient mice. We conclude from our data in vitro and in vivo that ISG12 is a novel modulator of innate immune responses regulating anti-inflammatory nuclear receptors such as NR4A1.

scholarly journals Autoinhibition and relief mechanism by the proteolytic processing of Toll-like receptor 8

2016 ◽  
Vol 113 (11) ◽  
pp. 3012-3017 ◽  
Author(s):  
Hiromi Tanji ◽  
Umeharu Ohto ◽  
Yuji Motoi ◽  
Takuma Shibata ◽  
Kensuke Miyake ◽  
...  
Keyword(s):  
Immune Responses ◽  
Molecular Basis ◽  
Crystallographic Analysis ◽  
Proteolytic Processing ◽  
Innate Immune ◽  
Structural Studies ◽  
Innate Immune Responses ◽  
Leucine Rich Repeat ◽  
Toll Like Receptor ◽  
Loop Region

Toll-like receptor 8 (TLR8) senses single-stranded RNA (ssRNA) and initiates innate immune responses. TLR8 requires proteolytic cleavage at the loop region (Z-loop) between leucine-rich repeat (LRR) 14 and LRR15 for its activation. However, the molecular basis of Z-loop processing remains unknown. To elucidate the mechanism of Z-loop processing, we performed biochemical and structural studies of how the Z-loop affects the function of TLR8. TLR8 with the uncleaved Z-loop is unable to form a dimer, which is essential for activation, irrespective of the presence of agonistic ligands. Crystallographic analysis revealed that the uncleaved Z-loop located on the ascending lateral face prevents the approach of the dimerization partner by steric hindrance. This autoinhibition mechanism of dimerization by the Z-loop might be occurring in the proteins of the same subfamily, TLR7 and TLR9.

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