RESUMO
BACKGROUND: COVID-19 clinical course is highly variable and secondary infections contribute to COVID-19 complexity. Early detection of secondary infections is clinically relevant for patient outcome. Procalcitonin (PCT) and C-reactive protein (CRP) are the most used biomarkers of infections. Pentraxin 3 (PTX3) is an acute phase protein with promising performance as early biomarker in infections. In patients with COVID-19, PTX3 plasma concentrations at hospital admission are independent predictor of poor outcome. In this study, we assessed whether PTX3 contributes to early identification of co-infections during the course of COVID-19. METHODS: We analyzed PTX3 levels in patients affected by COVID-19 with (n = 101) or without (n = 179) community or hospital-acquired fungal or bacterial secondary infections (CAIs or HAIs). FINDINGS: PTX3 plasma concentrations at diagnosis of CAI or HAI were significantly higher than those in patients without secondary infections. Compared to PCT and CRP, the increase of PTX3 plasma levels was associated with the highest hazard ratio for CAIs and HAIs (aHR 11.68 and 24.90). In multivariable Cox regression analysis, PTX3 was also the most significant predictor of 28-days mortality or intensive care unit admission of patients with potential co-infections, faring more pronounced than CRP and PCT. INTERPRETATION: PTX3 is a promising predictive biomarker for early identification and risk stratification of patients with COVID-19 and co-infections. FUNDING: Dolce & Gabbana fashion house donation; Ministero della Salute for COVID-19; EU funding within the MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT) and MUR PNRR Italian network of excellence for advanced diagnosis (Project no. PNC-E3-2022-23683266 PNC-HLS-DA); EU MSCA (project CORVOS 860044).
Assuntos
Biomarcadores , Proteína C-Reativa , COVID-19 , Coinfecção , SARS-CoV-2 , Componente Amiloide P Sérico , Humanos , COVID-19/sangue , COVID-19/diagnóstico , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Componente Amiloide P Sérico/metabolismo , Biomarcadores/sangue , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Infecções Bacterianas/sangue , Infecções Bacterianas/diagnóstico , Pró-Calcitonina/sangue , Prognóstico , Micoses/sangue , Micoses/diagnóstico , Idoso de 80 Anos ou maisRESUMO
Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. This study aims to dissect the role of neutrophils in these pathologic contexts by using a rigorous genetic approach. Neutrophil-deficient mice (Csf3r-/- mice) were used in classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histologic, cellular, and molecular analyses coupled with adoptive cell transfer. We also performed correlative analyses using human datasets. Csf3r-/- mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared with control Csf3r+/+ mice and adoptive transfer of neutrophils in Csf3r-/- mice reverted the phenotype. In colitis, Csf3r-/- mice showed increased bacterial invasion and a reduced number of healing ulcers in the colon, indicating a compromised regenerative capacity of epithelial cells. Neutrophils were essential for γδ T-cell polarization and IL22 production. In patients with ulcerative colitis, expression of CSF3R was positively correlated with IL22 and IL23 expression. Moreover, gene signatures associated with epithelial-cell development, proliferation, and antimicrobial response were enriched in CSF3Rhigh patients. Our data support a model where neutrophils mediate protection against intestinal inflammation and colitis-associated colorectal cancer by controlling the intestinal microbiota and driving the activation of an IL22-dependent tissue repair pathway.
Assuntos
Colite Ulcerativa , Neoplasias Associadas a Colite , Neutrófilos , Animais , Humanos , Camundongos , Carcinogênese , Colite/patologia , Colite Ulcerativa/metabolismo , Neoplasias Associadas a Colite/patologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismoRESUMO
Breast implants are extensively employed for both reconstructive and esthetic purposes. However, the safety of breast implants with textured surfaces has been questioned, owing to a potential correlation with anaplastic large-cell lymphoma and the recurrence of breast cancer. This study investigates the immune response elicited by different prosthetic surfaces, focusing on the comparison between macrotextured and microtextured breast implants. Through the analysis of intraoperatively harvested periprosthetic fluids and cell culture experiments on surface replicas, we demonstrate that macrotextured surfaces elicit a more pronounced chronic-like activation of leucocytes and an increased release of inflammatory cytokines, in contrast to microtextured surfaces. In addition, in vitro fluorescent imaging of leucocytes revealed an accumulation of lymphocytes within the cavities of the macrotextured surfaces, indicating that the physical entrapment of these cells may contribute to their activation. These findings suggest that the topography of implant surfaces plays a significant role in promoting a chronic-like inflammatory environment, which could be a contributing factor in the development of lymphomas associated with a wide range of implantable devices.
Assuntos
Implante Mamário , Implantes de Mama , Neoplasias da Mama , Linfoma Anaplásico de Células Grandes , Humanos , Feminino , Implantes de Mama/efeitos adversos , Linfoma Anaplásico de Células Grandes/etiologia , Linfoma Anaplásico de Células Grandes/cirurgiaRESUMO
Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) play pivotal role in immunity and inflammation and are expressed by most cell types including cells of both the innate and adaptive immune system. In this context, IL-1 superfamily members are also important players in regulating function and differentiation of adaptive and innate lymphoid cells. This system is tightly regulated in order to avoid uncontrolled activation, which may lead to detrimental inflammation contributing to autoimmune or allergic responses. IL-1R8 (also known as TIR8 or SIGIRR) is a member of the IL-1R family that acts as a negative regulator dampening ILR and TLR signaling and as a co-receptor for human IL-37. Human and mouse NK cells, that are key players in immune surveillance of tumors and infections, express high level of IL-1R8. In this review, we will summarize our current understanding on the structure, expression and function of IL-1R8 and we will also discuss the emerging role of IL-1R8 as an important checkpoint regulating NK cells function in pathological conditions including cancer and viral infections.
Assuntos
Imunidade Inata , Neoplasias , Animais , Humanos , Inflamação , Células Matadoras Naturais , Neoplasias/metabolismo , Receptores de Interleucina-1/metabolismoRESUMO
Interleukin-1 (IL-1) is a primary cytokine of innate immunity and inflammation. IL-1 belongs to a complex family including ligands with agonist activity, receptor antagonists, and an anti-inflammatory cytokine. The receptors for these ligands, the IL-1 Receptor (IL-1R) family, include signaling receptor complexes, decoy receptors, and negative regulators. Agonists and regulatory molecules co-evolved, suggesting the evolutionary relevance of a tight control of inflammatory responses, which ensures a balance between amplification of innate immunity and uncontrolled inflammation. IL-1 family members interact with innate immunity cells promoting innate immunity, as well as with innate and adaptive lymphoid cells, contributing to their differentiation and functional polarization and plasticity. Here we will review the properties of two key regulatory receptors of the IL-1 system, IL-1R2, the first decoy receptor identified, and IL-1R8, a pleiotropic regulator of different IL-1 family members and co-receptor for IL-37, the anti-inflammatory member of the IL-1 family. Their complex impact in pathology, ranging from infections and inflammatory responses, to cancer and neurologic disorders, as well as clinical implications and potential therapeutic exploitation will be presented.
Assuntos
Imunidade Inata , Inflamação/imunologia , Receptores Tipo II de Interleucina-1/metabolismo , Receptores de Interleucina-1/metabolismo , Animais , Humanos , Imunomodulação , Neoplasias/imunologia , Doenças do Sistema Nervoso/imunologiaRESUMO
BACKGROUND: Natural killer (NK) cells require a functional lytic granule machinery to mediate effective antitumor responses. Evading the lytic cargo deployed at the immune synapse (IS) could be a critical step for cancer progression through yet unidentified mechanisms. METHODS: NK cell antibody-dependent cellular cytotoxicity (ADCC) is a major determinant of the clinical efficacy of some therapeutic antibodies including the anti-HER2 Trastuzumab. Thus, we screened sera of Trastuzumab-resistant HER2 +patients with breast cancer for molecules that could inhibit NK cell ADCC. We validated our findings in vitro using cytotoxicity assays and confocal imaging of the lytic granule machinery and in vivo using syngeneic and xenograft murine models. RESULTS: We found that sera from Trastuzumab-refractory patients could inhibit healthy NK cell ADCC in vitro. These sera contained high levels of the inflammatory protein chitinase 3-like 1 (CHI3L1) compared with sera from responders and healthy controls. We demonstrate that recombinant CHI3L1 inhibits both ADCC and innate NK cell cytotoxicity. Mechanistically, CHI3L1 prevents the correct polarization of the microtubule-organizing center along with the lytic granules to the IS by hindering the receptor of advanced glycation end-products and its downstream JNK signaling. In vivo, CHI3L1 administration drastically impairs the control of NK cell-sensitive tumors, while CHI3L1 blockade synergizes with ADCC to cure mice with HER2 +xenografts. CONCLUSION: Our work highlights a new paradigm of tumor immune escape mediated by CHI3L1 which acts on the cytotoxic machinery and prevents granule polarization. Targeting CHI3L1 could mitigate immune escape and potentiate antibody and cell-based immunotherapies.
Assuntos
Proteína 1 Semelhante à Quitinase-3/metabolismo , Evasão da Resposta Imune/imunologia , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias/genética , Animais , Feminino , Humanos , CamundongosRESUMO
Human Vδ2 cells are innate-like γδ T effectors performing potent immune surveillance against tumors. The constitutive expression of NKG2A identifies a subset of Vδ2 T cells licensed with an intrinsic hyper-responsiveness against cancer. Indeed, the transcriptomic profiles of NKG2A+ and NKG2A- cells characterize two distinct "intralineages" of Vδ2 T lymphocytes that appear early during development, keep their phenotypes, and show self-renewal capabilities in adult life. The hyper-responsiveness of NKG2A+ Vδ2 T cells is counterbalanced by the inhibitory signaling delivered by human leukocyte antigen E (HLA-E) expressed on malignant cells as a tumor-escape mechanism. However, either masking or knocking out NKG2A restores the capacity of Vδ2 T cells to exert the highest effector functions even against HLA-E+ tumors. This is highly relevant in the clinic, as the different degrees of engagement of the NKG2A-HLA-E checkpoint in hepatocellular carcinoma, glioblastoma, and non-small cell lung cancer directly impact patients' overall survival. These findings open avenues for developing combined cellular and immunologic anticancer therapies.
Assuntos
Citotoxicidade Imunológica , Linfócitos Intraepiteliais/metabolismo , Ativação Linfocitária , Linfócitos do Interstício Tumoral/metabolismo , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Idoso , Estudos de Casos e Controles , Proliferação de Células , Autorrenovação Celular , Técnicas de Cocultura , Citocinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Inata , Lactente , Linfócitos Intraepiteliais/imunologia , Células K562 , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Fenótipo , Receptores de Antígenos de Linfócitos T gama-delta/genética , Transdução de SinaisRESUMO
Complement has emerged as a component of tumor promoting inflammation. We conducted a systematic assessment of the role of complement activation and effector pathways in sarcomas. C3-/-, MBL1/2-/- and C4-/- mice showed reduced susceptibility to 3-methylcholanthrene sarcomagenesis and transplanted sarcomas, whereas C1q and factor B deficiency had marginal effects. Complement 3a receptor (C3aR), but not C5aR1 and C5aR2, deficiency mirrored the phenotype of C3-/- mice. C3 and C3aR deficiency were associated with reduced accumulation and functional skewing of tumor-associated macrophages, increased T cell activation and response to anti-PD-1 therapy. Transcriptional profiling of sarcoma infiltrating macrophages and monocytes revealed the enrichment of MHC II-dependent antigen presentation pathway in C3-deficient cells. In patients, C3aR expression correlated with a macrophage population signature and C3 deficiency-associated signatures predicted better clinical outcome. These results suggest that the lectin pathway and C3a/C3aR axis are key components of complement and macrophage-mediated sarcoma promotion and immunosuppression.
Assuntos
Lectinas , Receptores de Complemento/metabolismo , Sarcoma , Animais , Ativação do Complemento/fisiologia , Humanos , Terapia de Imunossupressão , Lectinas/metabolismo , Camundongos , Monócitos/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Sarcoma/tratamento farmacológicoRESUMO
Glycosphingolipids are important components of the plasma membrane where they modulate the activities of membrane proteins including signalling receptors. Glycosphingolipid synthesis relies on competing reactions catalysed by Golgi-resident enzymes during the passage of substrates through the Golgi cisternae. The glycosphingolipid metabolic output is determined by the position and levels of the enzymes within the Golgi stack, but the mechanisms that coordinate the intra-Golgi localisation of the enzymes are poorly understood. Here, we show that a group of sequentially-acting enzymes operating at the branchpoint among glycosphingolipid synthetic pathways binds the Golgi-localised oncoprotein GOLPH3. GOLPH3 sorts these enzymes into vesicles for intra-Golgi retro-transport, acting as a component of the cisternal maturation mechanism. Through these effects, GOLPH3 controls the sub-Golgi localisation and the lysosomal degradation rate of specific enzymes. Increased GOLPH3 levels, as those observed in tumours, alter glycosphingolipid synthesis and plasma membrane composition thereby promoting mitogenic signalling and cell proliferation. These data have medical implications as they outline a novel oncogenic mechanism of action for GOLPH3 based on glycosphingolipid metabolism.
Assuntos
Proliferação de Células , Glicoesfingolipídeos/biossíntese , Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Células Cultivadas , Células HeLa , Humanos , Lisossomos/metabolismo , Proteínas de Membrana/genética , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Transdução de SinaisRESUMO
Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
Assuntos
Proteína C-Reativa/genética , COVID-19/genética , Perfilação da Expressão Gênica/métodos , Macrófagos/metabolismo , SARS-CoV-2/isolamento & purificação , Componente Amiloide P Sérico/genética , Células A549 , Adulto , Proteína C-Reativa/metabolismo , COVID-19/epidemiologia , COVID-19/virologia , Linhagem Celular Tumoral , Células Cultivadas , Estudos de Coortes , Células Endoteliais/metabolismo , Epidemias , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Neutrófilos/metabolismo , Prognóstico , SARS-CoV-2/fisiologia , Componente Amiloide P Sérico/metabolismoRESUMO
Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.
Assuntos
Resistência à Doença , Neoplasias/patologia , Neutrófilos/imunologia , Sarcoma/patologia , Linfócitos T/metabolismo , Animais , Cromonas/toxicidade , Resistência à Doença/imunologia , Humanos , Imunidade Inata , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Estimativa de Kaplan-Meier , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/mortalidade , Infiltração de Neutrófilos , Neutrófilos/citologia , Neutrófilos/metabolismo , Receptores de Fator Estimulador de Colônias/metabolismo , Sarcoma/induzido quimicamente , Sarcoma/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente TumoralRESUMO
Chronic inflammation, including that driven by autoimmunity, is associated with the development of B-cell lymphomas. IL1R8 is a regulatory receptor belonging to the IL1R family, which negatively regulates NF-κB activation following stimulation of IL1R or Toll-like receptor family members. IL1R8 deficiency is associated with the development of severe autoimmune lupus-like disease in lpr mice. We herein investigated whether concomitant exacerbated inflammation and autoimmunity caused by the deficiency of IL1R8 could recapitulate autoimmunity-associated lymphomagenesis. We thus monitored B-cell lymphoma development during the aging of IL1R8-deficient lpr mice, observing an increased lymphoid cell expansion that evolved to diffuse large B-cell lymphoma (DLBCL). Molecular and gene-expression analyses showed that the NF-κB pathway was constitutively activated in Il1r8 -/-/lpr B splenocytes. In human DLBCL, IL1R8 had reduced expression compared with normal B cells, and higher IL1R8 expression was associated with a better outcome. Thus, IL1R8 silencing is associated with increased lymphoproliferation and transformation in the pathogenesis of B-cell lymphomas associated with autoimmunity.
Assuntos
Autoimunidade/genética , Suscetibilidade a Doenças , Linfoma/etiologia , Receptores de Interleucina-1/deficiência , Animais , Biomarcadores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Predisposição Genética para Doença , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imuno-Histoquímica , Linfoma/metabolismo , Linfoma/patologia , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos , NF-kappa B/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismoRESUMO
Long non-coding RNAs (lncRNAs) are post-transcriptional and epigenetic regulators, whose implication in neurodegenerative and autoimmune diseases remains poorly understood. We analyzed publicly available microarray data sets to identify dysregulated lncRNAs in multiple sclerosis (MS), a neuroinflammatory autoimmune disease. We found a consistent upregulation in MS of the lncRNA MALAT1 (2.7-fold increase; meta-analysis, P = 1.3 × 10-8; 190 cases, 182 controls), known to regulate alternative splicing (AS). We confirmed MALAT1 upregulation in two independent MS cohorts (1.5-fold increase; P < 0.01; 59 cases, 50 controls). We hence performed MALAT1 overexpression/knockdown in cell lines, demonstrating that its modulation impacts on endogenous expression of splicing factors (HNRNPF and HNRNPH1) and on AS of MS-associated genes (IL7R and SP140). Minigene-based splicing assays upon MALAT1 modulation recapitulated IL7R and SP140 isoform unbalances observed in patients. RNA-sequencing of MALAT1-knockdown Jurkat cells further highlighted MALAT1 role in splicing (approximately 1100 significantly-modulated AS events) and revealed its contribution to backsplicing (approximately 50 differentially expressed circular RNAs). Our study proposes a possible novel role for MALAT1 dysregulation and the consequent AS alteration in MS pathogenesis, based on anomalous splicing/backsplicing profiles of MS-relevant genes.
Assuntos
Processamento Alternativo , Esclerose Múltipla/genética , Neoplasias/genética , RNA Circular , RNA Longo não Codificante/genética , Transcriptoma , Regulação da Expressão Gênica , Humanos , Interferência de RNARESUMO
NK cells are innate lymphoid cells, which play a key role in the immune response to cancer and pathogens and participate in the shaping of adaptive immunity. NK cells engage in a complex bidirectional interaction with myelomonocytic cells. In particular, macrophages, dendritic cells and neutrophils promote differentiation and effector function of NK cells and, on the other hand, myelomonocytic cells express triggers of checkpoint blockade (eg PD-L1) and other immunosuppressive molecules, which negatively regulate NK cell function. In addition, NK cells express high levels of IL-1R8, which acts as a checkpoint for IL-18 driven differentiation and activation of NK cells. Evidence suggests that targeting the myeloid cell-NK cell crosstalk unleashes effective anti-tumour and anti-viral resistance.
Assuntos
Células Matadoras Naturais/fisiologia , Células Mieloides/fisiologia , Neoplasias/imunologia , Viroses/imunologia , Animais , Antígeno B7-H1/metabolismo , Comunicação Celular , Humanos , Imunidade Inata , Interleucina-18/metabolismo , Receptores de Interleucina-1/metabolismo , Yin-YangRESUMO
Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) are key players in immunity and inflammation and are tightly regulated at different levels. Most cell types, including cells of the innate and adaptive immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R2 and IL-1R8 (also known as TIR8 or SIGIRR) are members of the ILR family acting as negative regulators of the IL-1 system. IL-1R2 binds IL-1 and the accessory protein IL-1RAcP without activating signaling and can be released as a soluble form (sIL-1R2), thus modulating IL-1 availability for the signaling receptor. IL-1R8 dampens ILR- and TLR-mediated cell activation and it is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R2 and IL-1R8, focusing on their role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation. We also address the emerging evidence regarding the role of IL-1R8 as a crucial checkpoint molecule in NK cells in anti-cancer and antiviral activity and the potential therapeutic implications of IL-1R8 blockade in specific pathological contexts.