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2.
JCI Insight ; 9(16)2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39024563

RESUMEN

Gain-of-function mutations in the dsDNA sensing adaptor STING lead to a severe autoinflammatory syndrome known as STING-associated vasculopathy with onset in infancy (SAVI). Patients with SAVI develop interstitial lung disease (ILD) and produce autoantibodies that are commonly associated with systemic autoimmune diseases. Mice expressing the most common SAVI mutation, STING V154M (VM), similarly develop ILD but exhibit severe T and B cell lymphopenia and low serum Ig titers, and they lack autoantibodies. Importantly, lethally irradiated VM hosts reconstituted with WT stem cells (WT→VM) still develop ILD. In this study, we find that WT→VM chimeras had restored B cell function, produced autoantibodies, and thereby recapitulated the loss of tolerance seen in patients with SAVI. Lymphocytes derived from both WT and BCR or TCR transgenic (Tg) donors accumulated in the extravascular lung tissue of WT+Tg→VM mixed chimeras, but lymphocyte activation and germinal center formation required WT cells with a diverse repertoire. Furthermore, when T cells isolated from the WT→VM chimeras were adoptively transferred to naive Rag1-deficient secondary hosts, they trafficked to the lung and recruited neutrophils. Overall, these findings indicated that VM expression by radioresistant cells promoted the activation of autoreactive B cells and T cells that then differentiated into potentially pathogenic effector subsets.


Asunto(s)
Mutación con Ganancia de Función , Activación de Linfocitos , Proteínas de la Membrana , Animales , Ratones , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Activación de Linfocitos/inmunología , Pulmón/inmunología , Pulmón/patología , Autoanticuerpos/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/inmunología , Tolerancia a Radiación/genética , Tolerancia a Radiación/inmunología , Ratones Transgénicos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Femenino , Humanos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad
3.
bioRxiv ; 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39071327

RESUMEN

Patients with biallelic hypomorphic mutation in DNASE2 develop systemic autoinflammation and early-onset liver fibrosis. Prior studies showed that Dnase2 -/- Ifnar -/- double knockout (DKO) mice develop Type I IFN-independent liver inflammation, but immune mechanisms were unclear. We now show that DKO mice recapitulate many features of human autoimmune hepatitis (AIH), including periportal and interstitial inflammation and fibrosis and elevated ALT. Infiltrating cells include CD8+ tissue resident memory T cells, type I innate lymphoid cells, and inflammatory monocyte/macrophage cells that replace the Kupffer cell pool. Importantly, TLR9 expression by bone marrow-derived cells is required for the the development of AIH. TLR9 is highly expressed by inflammatory myeloid cells but not long-lived Kupffer cells. Furthermore, the initial recruitment of TLR9 expressing monocytes and subsequent activation of lymphocytes requires IFNγ signaling. These findings highlight a critical role of feed forward loop between TLR9 expressing monocyte-lineage cells and IFNg producing lymphocytes in autoimmune hepatitis.

4.
Res Sq ; 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38947028

RESUMEN

Background-: Glaucoma is a complex multifactorial disease where apoptosis and inflammation represent two key pathogenic mechanisms. However, the relative contribution of apoptosis versus inflammation in axon degeneration and death of retinal ganglion cells (RGCs) is not well understood. In glaucoma, caspase-8 is linked to RGC apoptosis, as well as glial activation and neuroinflammation. To uncouple these two pathways and determine the extent to which caspase-8-mediated inflammation and/or apoptosis contributes to the death of RGCs, we used the caspase-8 D387A mutant mouse (Casp8 DA/DA ) in which a point mutation in the auto-cleavage site blocks caspase-8-mediated apoptosis but does not block caspase-8-mediated inflammation. Methods-: Intracameral injection of magnetic microbeads was used to elevate the intraocular pressure (IOP) in wild-type, Fas deficient Faslpr, and Casp8 DA/DA mice. IOP was monitored by rebound tonometry. Two weeks post microbead injection, retinas were collected for microglia activation analysis. Five weeks post microbead injection, visual acuity and RGC function were assessed by optometer reflex (OMR) and pattern electroretinogram (pERG), respectively. Retina and optic nerves were processed for RGC and axon quantification. Two- and five-weeks post microbead injection, expression of the necrosis marker, RIPK3, was assessed by qPCR. Results-: Wild-type, Faslpr, and Casp8 DA/DA mice showed similar IOP elevation as compared to saline controls. A significant reduction in both visual acuity and pERG that correlated with a significant loss of RGCs and axons was observed in wild-type but not in Faslpr mice. The Casp8 DA/DA mice displayed a significant reduction in visual acuity and pERG amplitude and loss of RGCs and axons similar to that in wild-type mice. Immunostaining revealed equal numbers of activated microglia, double positive for P2ry12 and IB4, in the retinas from microbead-injected wild-type and Casp8 DA/DA mutant mice. qPCR analysis revealed no induction of RIPK3 in wild-type or Casp8 DA/DA mice at two- or five-weeks post microbead injection. Conclusions-: Our results demonstrate that caspase-8-mediated extrinsic apoptosis is not involved in the death of RGCs in the microbead-induced mouse model of glaucoma implicating caspase-8-mediated inflammation, but not apoptosis, as the driving force in glaucoma progression. Taken together, these results identify the caspase-8-mediated inflammatory pathway as a potential target for neuroprotection in glaucoma.

5.
Res Sq ; 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38766158

RESUMEN

Neovascular age-related macular degeneration (AMD), results from choroidal neovascularization (CNV), retinal edema and loss of photoreceptors. Previous studies suggested that Fas Ligand (FasL) on retinal pigment epithelial cells inhibited CNV by inducing apoptosis of infiltrating Fas+ vascular endothelial cells. However, induction of apoptosis depends on membrane-bound (mFasL) while the FasL cleavage product (sFasL) is neuroprotective. To better understand how FasL regulates the development of CNV, we used a mouse model of laser CNV to evaluate the development of CNV in mice with a FasL cleavage site mutation (ΔCS) and can only express the membrane-bound form of FasL. There was no significant difference in CNV size and area of vascular leakage in homozygous FasLΔCS/ΔCS mice when compared to wild type mice. Unexpectedly, heterozygous FasLΔCS/WT mice developed significantly less vascular leakage and showed accelerated neovessel maturation. However, CNV was not prevented in heterozygous FasLΔCS/WT mice if the Fas receptor was deleted in myeloid cells (FasLΔCS/+ Fasflox/flox CreLysM). Thus, FasL-mediated CNV inhibition depends on the extent of FasL cleavage, and on FasL engagement of Fas+ myeloid cells. Moreover, accelerated neovessel maturation prevents vascular leakage in AMD.

6.
Cell Rep ; 43(4): 114114, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38625791

RESUMEN

Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders.


Asunto(s)
Células Endoteliales , Mutación con Ganancia de Función , Pulmón , Proteínas de la Membrana , Animales , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Ratones , Pulmón/patología , Pulmón/metabolismo , Linfocitos/metabolismo , Enfermedades Pulmonares Intersticiales/patología , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/metabolismo , Ratones Endogámicos C57BL , Humanos
7.
J Exp Med ; 220(12)2023 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-37773045

RESUMEN

Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides. The in vivo production of CXCL4 thereby impedes both TLR9 responses in B cells and the establishment of central B cell tolerance. We conclude that TLR9 plays an essential early tolerogenic function required for the establishment of central B cell tolerance and that correcting defective TLR9 function in B cells from SSc patients may represent a novel therapeutic strategy to restore B cell tolerance.


Asunto(s)
Factor Plaquetario 4 , Esclerodermia Sistémica , Receptor Toll-Like 9 , Animales , Humanos , Ratones , Linfocitos B , Ligandos , Factor 88 de Diferenciación Mieloide/metabolismo , Factor Plaquetario 4/metabolismo , Esclerodermia Sistémica/metabolismo , Receptor Toll-Like 7 , Receptor Toll-Like 9/metabolismo
8.
Immunity ; 56(10): 2373-2387.e8, 2023 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-37714151

RESUMEN

Immunoglobulin A (IgA) maintains commensal communities in the intestine while preventing dysbiosis. IgA generated against intestinal microbes assures the simultaneous binding to multiple, diverse commensal-derived antigens. However, the exact mechanisms by which B cells mount broadly reactive IgA to the gut microbiome remains elusive. Here, we have shown that IgA B cell receptor (BCR) is required for B cell fitness during the germinal center (GC) reaction in Peyer's patches (PPs) and for generation of gut-homing plasma cells (PCs). We demonstrate that IgA BCR drove heightened intracellular signaling in mouse and human B cells, and as a consequence, IgA+ B cells received stronger positive selection cues. Mechanistically, IgA BCR signaling offset Fas-mediated death, possibly rescuing low-affinity B cells to promote a broad humoral response to commensals. Our findings reveal an additional mechanism linking BCR signaling, B cell fate, and antibody production location, which have implications for how intestinal antigen recognition shapes humoral immunity.


Asunto(s)
Linfocitos B , Ganglios Linfáticos Agregados , Ratones , Humanos , Animales , Antígenos/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Inmunoglobulina A , Mucosa Intestinal
9.
bioRxiv ; 2023 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-37546720

RESUMEN

Gain-of-function mutations in the dsDNA sensing adaptor STING lead to a severe autoinflammatory syndrome known as STING-associated vasculopathy with onset in Infancy (SAVI). SAVI patients develop interstitial lung disease (ILD) and commonly produce anti-nuclear antibodies (ANAs), indicative of concomitant autoimmunity. Mice heterozygous for the most common SAVI mutation, V154M (VM), also develop ILD, triggered by nonhematopoietic VM cells, but exhibit severe peripheral lymphopenia, low serum Ig titers and fail to produce autoantibodies. In contrast, we now show that lethally irradiated VM mice reconstituted with WT stem cells (WT→VM chimeras) develop ANAs and lung-reactive autoantibodies associated with accumulation of activated lymphocytes and formation of germinal centers in lung tissues. Moreover, when splenocytes from WT→VM chimeras were adoptively transferred into unmanipulated Rag1 -/- mice, donor T cells accumulated in the lung. Overall, these findings demonstrate that expression of the VM mutation in non-hematopoietic cells can promote the activation of immunocompetent autoreactive lymphocytes. Summary: Chimeric mice expressing STING only in non-hematopoietic cells develop systemic and lung directed autoimmunity which recapitulates what is seen in pediatric patients with SAVI disease.

10.
bioRxiv ; 2023 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-37547024

RESUMEN

Patients afflicted with STING gain-of-function mutations frequently present with debilitating interstitial lung disease ( ILD ) that is recapitulated in mice expressing the STING V154M mutation ( VM ). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in the initiation of ILD. To identify STING-expressing non-hematopoietic cell types relevant to ILD, we generated a conditional knock-in ( CKI ) model in which expression of the VM allele was directed to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted expression of the mutant allele resulted in the recruitment of immune cells to the lung and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of SAVI patients or patients afflicted with other ILD-related disorders. Summary: Patients with STING gain-of-function (GOF) mutations develop life-threatening lung autoinflammation. In this study, Gao et al. utilize a mouse model of conditional STING GOF to demonstrate a role for endothelial STING GOF in initiating immune cell recruitment into lung tissues of SAVI mice.

11.
Immunohorizons ; 7(8): 577-586, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37555846

RESUMEN

Phospholipase D4 (PLD4) is an endolysosomal exonuclease of ssRNA and ssDNA, rather than a phospholipase as its name suggests. Human polymorphisms in the PLD4 gene have been linked by genome-wide association studies to systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, B6.129 Pld4-/- mice develop features of a distinct disease, macrophage activation syndrome, which is reversed in mice mutated in TLR9. In this article, we compare a Pld4 null mutant identified on the BALB/c background, Pld4thss/thss, which has distinct phenotypes: short stature, thin hair, and features of systemic lupus erythematosus. All phenotypes analyzed were largely normalized in Pld4thss/thssTlr9-/- mice. Thus, Pld4thss/thss represents a rare model in which mouse lupus etiology is TLR9 dependent. Compared with PLD4-deficient B6 mice, Pld4thss/thss mice had elevated levels of serum IgG, IgG anti-dsDNA autoantibodies, BAFF, and IFN-γ and elevated B cell numbers. Overall, the data suggest that PLD4 deficiency can lead to a diverse array of rheumatological abnormalities depending upon background-modifying genes, and that these diseases of PLD4 deficiency are largely driven by TLR9 recognition of ssDNA.


Asunto(s)
Lupus Eritematoso Sistémico , Receptor Toll-Like 9 , Animales , Humanos , Ratones , Exonucleasas/genética , Estudio de Asociación del Genoma Completo , Inmunoglobulina G/genética , Lupus Eritematoso Sistémico/genética , Fosfolipasas , Receptor Toll-Like 9/genética
12.
Curr Opin Immunol ; 80: 102280, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36638547

RESUMEN

The cyclic cyclic gaunosine monophosphate adenosine monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway senses cytosolic dsDNA and initiates immune responses against pathogens. It is also implicated in several auto-inflammatory diseases known as monogenic interferonopathies, specifically Three prime repair exonuclease 1 (Trex1) loss-of-function (LOF), Dnase2 LOF, and stimulator of interferon genes-associated-vasculopathy-with-onset-in-infancy (SAVI). Although monogenic interferonopathies have diverse clinical presentations, they are distinguished by the elevation of type-1 interferons (T1IFNs). However, animal models have demonstrated that T1IFNs contribute to only some disease outcomes and that cGAS-STING activation also promotes T1IFN-independent pathology. For example, while T1IFNs drive the immunopathology associated with Trex1 LOF, disease in Dnase2 LOF is partially independent of T1IFNs, while disease in SAVI appears to occur entirely independent of T1IFNs. Additionally, while the cGAS-STING pathway is well characterized in hematopoietic cells, these animal models point to important roles for STING activity in nonhematopoietic cells in disease. Together, these models illustrate the complex role that cGAS-STING-driven responses play in the pathogenesis of inflammatory diseases across tissues.


Asunto(s)
Interferón Tipo I , Animales , Interferón Tipo I/genética , Nucleótidos Cíclicos , Nucleotidiltransferasas/metabolismo , Inflamación/genética
13.
Aging Cell ; 21(10): e13705, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36056604

RESUMEN

Age-associated B cells (ABC) accumulate with age and are associated with autoimmunity and chronic infection. However, their contributions to acute infection in the aged and their developmental pathways are unclear. We find that the response against influenza A virus infection in aged mice is dominated by a Fas+ GL7- effector B cell population we call infection-induced ABC (iABC). Most iABC express IgM and include antibody-secreting cells in the spleen, lung, and bone marrow. We find that in response to influenza, IgD+ CD21- CD23- ABC are the precursors of iABC and become memory B cells. These IgD+ ABC develop in germ-free mice, so are independent of foreign antigen recognition. The response of ABC to influenza infection, resulting in iABC, is T cell independent and requires both extrinsic TLR7 and TLR9 signals. In response to influenza infection, IgD+ ABC can induce a faster recovery of weight and higher total anti-influenza IgG and IgM titers that can neutralize virus. Immunization with whole inactivated virus also generates iABC in aged mice. Thus, in unimmunized aged mice, whose other B and T cell responses have waned, IgD+ ABC are likely the naive B cells with the potential to become Ab-secreting cells and to provide protection from infection in the aged.


Asunto(s)
Vacunas contra la Influenza , Gripe Humana , Animales , Humanos , Ratones , Anticuerpos Antivirales , Inmunoglobulina D , Inmunoglobulina G , Inmunoglobulina M , Receptor Toll-Like 7 , Receptor Toll-Like 9 , Vacunas de Productos Inactivados , Linfocitos B , Linfocitos T
14.
Front Immunol ; 13: 883375, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35833127

RESUMEN

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by a strong IFN signature, normally associated with type I IFNs. However, increasing evidence points to an additional role for IFNγ, or at least a pathogenic T effector subset dependent on IFNγ, for disease progression. Nevertheless, Th2 effector subsets have also been implicated in CLE. We have now assessed the role of specific T cell subsets in the initiation and persistence of skin disease using a T cell-inducible murine model of CLE, dependent on KJ1-26 T cell recognition of an ovalbumin fusion protein. We found that only Th2-skewed cells, and not Th1-skewed cells, induced the development of skin lesions. However, we provide strong evidence that the Th2 disease-initiating cells convert to a more Th1-like functional phenotype in vivo by the time the skin lesions are apparent. This phenotype is maintained and potentiates over time, as T cells isolated from the skin, following a second induction of self-antigen, expressed more IFN-γ than T cells isolated at the time of the initial response. Transcriptional analysis identified additional changes in the KJ1-26 T cells at four weeks post injection, with higher expression levels of interferon stimulated genes (ISGs) including CXCL9, IRF5, IFIH1, and MX1. Further, injection of IFN-γ-/- T cells faied to induce skin disease in mice. We concluded that Th2 cells trigger skin lesion formation in CLE, and these cells switch to a Th1-like phenotype in the context of a TLR7-driven immune environment that is stable within the T cell memory compartment.


Asunto(s)
Dermatitis , Lupus Eritematoso Cutáneo , Animales , Dermatitis/metabolismo , Modelos Animales de Enfermedad , Inflamación/metabolismo , Factores Reguladores del Interferón/metabolismo , Ratones , Células TH1 , Células Th2
15.
Proc Natl Acad Sci U S A ; 119(25): e2202327119, 2022 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-35696583

RESUMEN

Pediatric patients with constitutively active mutations in the cytosolic double-stranded-DNA-sensing adaptor STING develop an autoinflammatory syndrome known as STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients have elevated interferon-stimulated gene expression and suffer from interstitial lung disease (ILD) with lymphocyte predominate bronchus-associated lymphoid tissue (BALT). Mice harboring SAVI mutations (STING V154M [VM]) that recapitulate human disease also develop lymphocyte-rich BALT. Ablation of either T or B lymphocytes prolongs the survival of SAVI mice, but lung immune aggregates persist, indicating that T cells and B cells can independently be recruited as BALT. VM T cells produced IFNγ, and IFNγR deficiency prolonged the survival of SAVI mice; however, T-cell-dependent recruitment of infiltrating myeloid cells to the lung was IFNγ independent. Lethally irradiated VM recipients fully reconstituted with wild type bone-marrow-derived cells still developed ILD, pointing to a critical role for VM-expressing radioresistant parenchymal and/or stromal cells in the recruitment and activation of pathogenic lymphocytes. We identified lung endothelial cells as radioresistant cells that express STING. Transcriptional analysis of VM endothelial cells revealed up-regulation of chemokines, proinflammatory cytokines, and genes associated with antigen presentation. Together, our data show that VM-expressing radioresistant cells play a key role in the initiation of lung disease in VM mice and provide insights for the treatment of SAVI patients, with implications for ILD associated with other connective tissue disorders.


Asunto(s)
Células Endoteliales , Enfermedades Pulmonares Intersticiales , Proteínas de la Membrana , Linfocitos T , Enfermedades Vasculares , Animales , Niño , Células Endoteliales/inmunología , Células Endoteliales/efectos de la radiación , Mutación con Ganancia de Función , Humanos , Interferón gamma/genética , Interferón gamma/metabolismo , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/inmunología , Depleción Linfocítica , Tejido Linfoide/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Tolerancia a Radiación , Linfocitos T/inmunología , Enfermedades Vasculares/genética , Enfermedades Vasculares/inmunología
16.
JCI Insight ; 6(22)2021 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-34618691

RESUMEN

BACKGROUNDInfluenza A virus (IAV) and SARS-CoV-2 are pandemic viruses causing millions of deaths, yet their clinical manifestations are distinctly different.METHODSWith the hypothesis that upper airway immune and epithelial cell responses are also distinct, we performed single-cell RNA sequencing (scRNA-Seq) on nasal wash cells freshly collected from adults with either acute COVID-19 or influenza or from healthy controls. We focused on major cell types and subtypes in a subset of donor samples.ResultsNasal wash cells were enriched for macrophages and neutrophils for both individuals with influenza and those with COVID-19 compared with healthy controls. Hillock-like epithelial cells, M2-like macrophages, and age-dependent B cells were enriched in COVID-19 samples. A global decrease in IFN-associated transcripts in neutrophils, macrophages, and epithelial cells was apparent in COVID-19 samples compared with influenza samples. The innate immune response to SARS-CoV-2 appears to be maintained in macrophages, despite evidence for limited epithelial cell immune sensing. Cell-to-cell interaction analyses revealed a decrease in epithelial cell interactions in COVID-19 and highlighted differences in macrophage-macrophage interactions for COVID-19 and influenza.ConclusionsOur study demonstrates that scRNA-Seq can define host and viral transcriptional activity at the site of infection and reveal distinct local epithelial and immune cell responses for COVID-19 and influenza that may contribute to their divergent disease courses.FundingMassachusetts Consortium on Pathogen Readiness, the Mathers Foundation, and the Department of Defense (W81XWH2110029) "COVID-19 Expansion for AIRe Program."


Asunto(s)
COVID-19 , Inmunidad Innata , Virus de la Influenza A , Gripe Humana , Macrófagos , RNA-Seq , SARS-CoV-2 , Adulto , COVID-19/genética , COVID-19/inmunología , Femenino , Humanos , Virus de la Influenza A/genética , Virus de la Influenza A/inmunología , Gripe Humana/genética , Gripe Humana/inmunología , Macrófagos/inmunología , Macrófagos/virología , Masculino , Lavado Nasal (Proceso) , SARS-CoV-2/genética , SARS-CoV-2/inmunología
17.
Immunity ; 54(6): 1137-1153.e8, 2021 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-34051146

RESUMEN

Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. We sought to delineate the functional role of STING in intestinal inflammation. Increased STING expression was a feature of intestinal inflammation in mice with colitis and in humans afflicted with inflammatory bowel disease. Mice bearing an allele rendering STING constitutively active exhibited spontaneous colitis and dysbiosis, as well as progressive chronic intestinal inflammation and fibrosis. Bone marrow chimera experiments revealed STING accumulation in intestinal macrophages and monocytes as the initial driver of inflammation. Depletion of Gram-negative bacteria prevented STING accumulation in these cells and alleviated intestinal inflammation. STING accumulation occurred at the protein rather than transcript level, suggesting post-translational stabilization. We found that STING was ubiquitinated in myeloid cells, and this K63-linked ubiquitination could be elicited by bacterial products, including cyclic di-GMP. Our findings suggest a positive feedback loop wherein dysbiosis foments the accumulation of STING in intestinal myeloid cells, driving intestinal inflammation.


Asunto(s)
Colitis/inmunología , Disbiosis/inmunología , Inmunidad Innata/inmunología , Proteínas de la Membrana/inmunología , Células Mieloides/inmunología , Ubiquitinación/inmunología , Animales , Estudios de Casos y Controles , Femenino , Humanos , Inflamación/inmunología , Intestinos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología
18.
Front Immunol ; 12: 605930, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33854495

RESUMEN

Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGASKOFaslpr mice on a pure MRL/Faslpr background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity.


Asunto(s)
Autoinmunidad , Susceptibilidad a Enfermedades , Lupus Eritematoso Sistémico/etiología , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/metabolismo , Transducción de Señal , Animales , Autoanticuerpos/inmunología , Autoinmunidad/genética , Biomarcadores , Modelos Animales de Enfermedad , Expresión Génica , Inmunofenotipificación , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Nucleotidiltransferasas/genética
19.
J Leukoc Biol ; 110(5): 965-977, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33565149

RESUMEN

Fas ligand (FasL) is best known for its ability to induce cell death in a wide range of Fas-expressing targets and to limit inflammation in immunoprivileged sites such as the eye. In addition, the ability of FasL to induce a much more extensive list of outcomes is being increasingly explored and accepted. These outcomes include the induction of proinflammatory cytokine production, T cell activation, and cell motility. However, the distinct and opposing functions of membrane-associated FasL (mFasL) and the C-terminal soluble FasL fragment (sFasL) released by metalloproteinase cleavage is less well documented and understood. Both mFasL and sFasL can form trimers that engage the trimeric Fas receptor, but only mFasL can form a multimeric complex in lipid rafts to trigger apoptosis and inflammation. By contrast, a number of reports have now documented the anti-apoptotic and anti-inflammatory activity of sFasL, pointing to a critical regulatory function of the soluble molecule. The immunomodulatory activity of FasL is particularly evident in ocular pathology where elimination of the metalloproteinase cleavage site and the ensuing increased expression of mFasL can severely exacerbate the extent of inflammation and cell death. By contrast, both homeostatic and increased expression of sFasL can limit inflammation and cell death. The mechanism(s) responsible for the protective activity of sFasL are discussed but remain controversial. Nevertheless, it will be important to consider therapeutic applications of sFasL for the treatment of ocular diseases such as glaucoma.


Asunto(s)
Oftalmopatías , Proteína Ligando Fas/metabolismo , Metaloproteasas/metabolismo , Animales , Humanos , Proteínas de la Membrana/metabolismo
20.
Viral Immunol ; 33(3): 246-249, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32286184

RESUMEN

Nucleic acid (NA) sensing receptors were first described in the context of host defense. We now know that some endosomal NA sensors play a critical role in the development of systemic autoimmune diseases such as systemic lupus erythematosus, whereas cytosolic Cyclic GMP-AMP Synthase/Stimulator of IFN Genes (cGAS/STING) DNA-detecting pathway has been associated with monogenic autoinflammatory interferonopathies such as Aicardi-Goutieres and Education; collaboration; communication STING-associated vasculopathy with onset in infancy (SAVI). DNaseII hypomorphic patients and DNase-/- IFNaR-/- (double knockout [DKO]) mice also develop an autoinflammatory syndrome associated with an interferon signature. We now add to the description of an unusual clinical manifestation of DKO mice that involves the accrual of trabecular bone in long bone marrow and the formation of ectopic bone within the spleen. This aberrant bone formation is lost not only in STING-deficient but also in Unc93b1-deficient mice and, therefore, depends on the interplay of cells expressing cytosolic and endosomal NA sensing receptors.


Asunto(s)
Endodesoxirribonucleasas/deficiencia , Inflamación/etiología , Interferones/genética , Ácidos Nucleicos/metabolismo , Osteogénesis , Transducción de Señal , Receptores Toll-Like/metabolismo , Animales , Endodesoxirribonucleasas/genética , Femenino , Interferones/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Noqueados , Receptores Toll-Like/genética
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