Silvano Sozzani

Sapienza University of Rome | la sapienza · Department of Molecular Medicine

Senescent cells have a profound impact on the surrounding microenvironment through the secretion of numerous bioactive molecules and inflammatory factors. The induction of therapy-induced senescence by anticancer drugs is known, but how senescent tumor cells influence the tumor immune landscape, particularly neutrophil activity, is still unclear. I...

Cancer progression is continuously controlled by the immune system which can identify and destroy nascent tumor cells or inhibit metastatic spreading. However, the immune system and its deregulated activity in the tumor microenvironment can also promote tumor progression favoring the outgrowth of cancers capable of escaping immune control, in a pr...

Plasmacytoid dendritic cells (pDCs) are the major producers of type I interferons (IFNs), which are essential to mount antiviral and antitumoral immune responses. To avoid exaggerated levels of type I IFNs, which pave the way to immune dysregulation and autoimmunity, pDC activation is strictly regulated by a variety of inhibitory receptors (IRs). I...

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require signal transducer and activator of transcription 4 (STAT4) to elicit rapid effector responses and protect against pathogens. By combining genetic and transcriptomic approaches, we uncovered divergent roles for STAT4 in regulating effector differentiation of these functionally...

Patterns of receptors for chemotactic factors regulate the homing of leukocytes to tissues. Here we report that the CCRL2/chemerin/CMKLR1 axis represents a selective pathway for the homing of NK cells to the lung. C-C motif Chemokine Receptor-Like 2 (CCRL2) is a non-signaling seven-transmembrane domain receptor able to control lung tumor growth. CC...

Background Circulating biomarkers with diagnostic and prognostic value in early Rheumatoid Arthritis (RA) are still an unmet need, especially for the subgroup of seronegative RA [e.g., negative for anti-citrullinated peptides autoantibodies (ACPA) and/or rheumatoid factors (RF)]. In a recent gene-based genome-wide association analysis (GWAS) study,...

The mechanisms of communication between the brain and the immune cells are still largely unclear. Here, we characterize the populations of resident natural killer (NK) cells and innate lymphoid cells (ILC) 1 in the meningeal dura layer of adult mice. We describe that ILC1/NK cell-derived interferon-γ and acetylcholine can contribute to the modulati...

Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [438, 437, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been ident...

Dendritic cells (DCs) exhibit a specialized antigen-presenting function and play crucial roles in both innate and adaptive immune responses. Due to their ability to cross-present tumor cell-associated antigens to naïve T cells, DCs are instrumental in the generation of specific T-cell-mediated antitumor effector responses in the control of tumor gr...

Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During ac...

Natural Killer (NK) cells are key innate effectors of antiviral immune response, and their activity changes in ageing and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated the age-related changes of NK cell phenotype and function during SARS-CoV-2 infection, by comparing adult and elderly patients both re...

Dendritic cells (DCs) are innate immune cells with a central role in immunity and tolerance. Under steady-state, DCs are scattered in tissues as resting cells. Upon infection or injury, DCs get activated and acquire the full capacity to prime antigen-specific CD4+ and CD8+ T cells, thus bridging innate and adaptive immunity. By secreting different...

Colorectal cancer (CRC) is one of the most common malignancies and leading causes of cancer-related deaths worldwide. Despite its complex pathogenesis and progression, CRC represents a well-fitting example of how the immune contexture can dictate the disease outcome. The presence of cytotoxic lymphocytes, both CD8+ T cells and natural killer (NK) c...

Hypoxia is a component of both physiological and pathological conditions, including inflammation, solid tumors, and lymphoid tissues, where O2 demand is not balanced by O2 supply. During their lifespan, dendritic cells (DCs) are exposed to different pO2 and activate different adaptive responses, including autophagy, to preserve their viability and...

Background Tanimilast is a novel and selective inhaled inhibitor of phosphodiesterase-4 in advanced clinical development for chronic obstructive pulmonary disease (COPD). Tanimilast is known to exert prominent anti-inflammatory activity when tested in preclinical experimental models as well as in human clinical studies. Recently, we have demonstrat...

Chemokine (C–C motif) receptor‐like 2 (CCRL2), is a seven transmembrane receptor closely related to the chemokine receptors CCR1, CCR2, CCR3, and CCR5. Nevertheless, CCRL2 is unable to activate conventional G‐protein dependent signaling and to induce cell directional migration. The only commonly accepted CCRL2 ligand is the non‐chemokine chemotacti...

Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases associated with chronic inflammatory conditions, such as COPD, psoriasis and atopic dermatitis. Tanimilast (international non-proprietary name of CHF6001) is a novel, potent and selective inhaled PDE4 inhibitor in advanced clinical development for the treatm...

The existence of extracellular miRNAs (ex-miRNAs) was first described in plasma and soon demonstrated in virtually all biological fluids. Ex-miRNAs are remarkably stable in harsh conditions, including high nuclease concentrations and extreme pH variations. This largely depends on their association with proteins protecting them from degradation, suc...

Chemerin is a multifunctional protein involved in the regulation of inflammation, metabolism, and tumorigenesis. It binds to three receptors, CMKLR1, GPR1 and CCRL2. CMKLR1 is a fully functional receptor mediating most of the known activities of chemerin. CCRL2 does not seem to couple to any intracellular signaling pathway and is presently consider...

NK cells are innate lymphoid cells endowed with cytotoxic capacity that play key roles in the immune surveillance of tumors. Increasing evidence indicates that NK cell anti-tumor response is shaped by bidirectional interactions with myeloid cell subsets such as dendritic cells (DCs) and macrophages. DC-NK cell crosstalk in the tumor microenvironmen...

CCRL2 belongs to the G protein-coupled receptor family and is one of the three chemerin receptors. It is considered as a non-signaling receptor, presenting chemerin to cells expressing the functional chemerin receptor ChemR23/CMKLR1 and possibly GPR1. In the present work, we investigate the role played by CCRL2 in mouse cancer models. Loss of funct...

Chemerin is a multifunctional protein involved in the regulation of inflammation, metabolism and tumorigenesis. It binds to three receptors, CMKLR1, GPR1 and CCRL2. CMKLR1 is a fully functional receptor mediating most of the known activities of chemerin. CCRL2 does not seem to couple to any intracellular signaling pathway, and is presently consider...

Type 1 innate lymphoid cells (ILC1) are tissue-resident lymphocytes which provide early protection against bacterial and viral infections. Discrete transcriptional states of ILC1 have been identified in homeostatic and pathological contexts. However, whether these states delineate ILC1 with different functional properties is not completely understo...

The inflammatory and IFN pathways of innate immunity play a key role in both resistance and pathogenesis of Coronavirus Disease 2019 (COVID-19). Innate sensors and SARS-CoV-2-Associated Molecular Patterns (SAMPs) remain to be completely defined. Here we identify single-stranded RNA (ssRNA) fragments from SARS-CoV-2 genome as direct activators of en...

Some bacterial pathogens can manipulate the angiogenic response, suppressing or inducing it for their own ends. In humans, B. henselae is associated with cat-scratch disease and vasculoproliferative disorders such as bacillary angiomatosis and bacillary peliosis. Although endothelial cells (ECs) support the pathogenesis of Bartonella , the mechanis...

Hypoxia is a key component of the tumor microenvironment (TME) and promotes not only tumor growth and metastasis, but also negatively affects infiltrating immune cells by impairing host immunity. Dendritic cells (DCs) are the most potent antigen-presenting cells and their biology is weakened in the TME in many ways, including the modulation of thei...

The inflammatory and IFN pathways of innate immunity play a key role in both resistance and pathogenesis of Coronavirus Disease 2019 (COVID-19). Innate sensors and SARS-CoV-2-Associated Molecular Patterns (SAMPs) remain to be completely defined. Here we identify single-stranded RNA (ssRNA) fragments from SARS-CoV-2 genome as direct activators of en...

CCRL2 is a seven-transmembrane domain receptor that belongs to the chemokine receptor family. At difference from other members of this family, CCRL2 does not promote chemotaxis and shares structural features with atypical chemokine receptors (ACKRs). However, CCRL2 also differs from ACKRs since it does not bind chemokines and is devoid of scavengin...

Background B henselae is in humans the aetiologic agent of cat-scratch disease and of the vasculoproliferative disorders bacillary angiomatosis and bacillary peliosis. Although endothelial cells are crucial in the pathogenesis other cell types function as reservoir and contribute to pathological angiogenesis. Among them, mesenchymal stromal cells (...

During their lifespan, dendritic cells (DCs) are exposed to different pO2 levels that affect their differentiation and functions. Autophagy is one of the adaptive responses to hypoxia with important implications for cell survival. While the autophagic machinery in DCs was shown to impact signaling of TLRs, its regulation by the MD-2/TLR4 ligand LPS...

Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [431, 430, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been ident...

Chemical induced carcinogenesis together with genetically engineered mouse models represent important approaches for the study of the complex mechanisms involving genotype and environmental factors in cancer development, including lung cancer. The induction of lung tumor in mice with urethane (ethyl carbamate) is considered a valuable model of Kras...

CD300e is a surface receptor, expressed by myeloid cells, involved in the tuning of immune responses. CD300e engagement was reported to provide the cells with survival signals, to trigger the expression of activation markers and the release of pro-inflammatory cytokines. Hence, CD300e is considered an immune activating receptor. In this study, we d...

Human Metapneumovirus (HMPV) is a major cause of lower respiratory tract infections. HMPV infection has been hypothesized to alter dendritic cell (DC) immune response; however, many questions regarding HMPV pathogenesis within the infected lung remain unanswered. Here, we show that HMPV productively infects human lung microvascular endothelial cell...

Dendritic cells (DCs) constitute a complex network of cell subsets with common functions but also with many divergent aspects. All dendritic cell subsets share the ability to prime T cell response and to undergo a complex trafficking program related to their stage of maturation and function. For these reasons, dendritic cells are implicated in a la...

Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [426, 425, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been ident...

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell ty...

Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [417, 416, 31]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been ident...

CCRL2 is a non-signaling seven-transmembrane domain receptor. CCRL2 binds chemerin, a protein that promotes chemotaxis of leukocytes, including macrophages and NK cells. In addition, CCRL2 controls the inflammatory response in different pathological settings, such as hypersensitivity, inflammatory arthritis, and experimental autoimmune encephalitis...

Osteopontin (OPN) is a pleiotropic cytokine produced both by immune and non-immune cells and active on different cellular targets. OPN production has been associated with several pathological conditions, including autoimmune diseases (e.g. lupus, multiple sclerosis and rheumatoid arthritis) and cancer. Emerging evidence suggests that the role of OP...

Since the discovery of the existence of microRNAs (miRNAs) in body fluids, the fascinating hypothesis that extracellular miRNAs may play a role in cell-to-cell signalling started to make its own way. In this review, we summarize the current knowledge that supports the role of miRNAs in the regulation of the immune response by an unconventional mech...

Persistent and excessive cytokine production is a hallmark of autoimmune diseases and may play a role in disease pathogenesis and amplification. Therefore, cytokine neutralization is a useful therapeutic strategy to treat immune-mediated conditions. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in diverse biolo...

Lymph node (LN) expansion during inflammation is essential to establish immune responses and relies on the development of blood and lymph vessels. Human dendritic cells (DCs), subdivided into two main subsets, namely conventional DCs (cDCs) and plasmacytoid DCs (pDCs), are professional antigen presenting cells endowed with the capability to produce...

Mesenchymal stromal cells (MSCs) exert immunosuppressive effects on immune cells including dendritic cells (DCs). However, many details of the bidirectional interaction of MSCs with DCs are still unsolved and information on key molecules by which DCs can modulate MSC functions is limited. Here, we report that osteopontin (OPN), a cytokine involved...

The excessive production of type I IFNs is a hallmark and a main pathogenic mechanism of many autoimmune diseases, including systemic lupus erythematosus (SLE). In these pathologies, the sustained secretion of type I IFNs is dependent on the improper activation of plasmacytoid DCs (pDCs) by self-nucleic acids. However, the nature and origin of pDC-...

Dendritic cells (DCs) are professional antigen-presenting cells responsible for the activation of specific T-cell responses and for the development of immune tolerance. Immature DCs reside in peripheral tissues and specialize in antigen capture, whereas mature DCs reside mostly in the secondary lymphoid organs where they act as antigen-presenting c...

C-C chemokine receptor-like 2 (CCRL2) is a non-signaling seven-transmembrane domain (7-TMD) receptor related to the atypical chemokine receptor (ACKR) family. ACKRs bind chemokines but do not activate G protein-dependent signaling or cell functions. ACKRs were shown to regulate immune functions in vivo by their ability to scavenge chemokines from t...

The tumor microenvironment consists of both malignant and non-malignant cells and a plethora of soluble mediators. Different types of tumors have specific tumor microenvironments characterized by distinct chemokines and chemotactic factors that influence leukocyte recruitment. The immune cell infiltrate continuously interacts with stroma cells and...

Dendritic cells (DCs) are professional antigen presenting cells displaying the unique capability to activate naïve T cells. DCs react to pathogen encounter also by the production of mediators of inflammation, including pro-inflammatory cytokines. Because of this complex role, any imbalance in DC function reflects into defective or exaggerated immun...

Key Points CCRL2 is required for CXCR2-dependent neutrophil recruitment. CCRL2 forms heterodimers with CXCR2 and regulates CXCR2 signaling.

Inflammatory reactions occurring in the central nervous system (CNS), known as neuroinflammation, are key components of the pathogenic mechanisms underlying several neurological diseases. The chemokine system plays a crucial role in the recruitment and activation of immune and non-immune cells in the brain, as well as in the regulation of microglia...

Autoimmune skin lesions are characterized by a complex cytokine milieu and by the accumulation of plasmacytoid dendritic cells (pDCs). Granzyme B (GrB) transcript is abundant in activated pDCs, though its mechanisms of regulation and biological role are largely unknown. Here we report that IL-21 was the only Th1/Th17 cytokine able to induce the exp...

Lymph node expansion during inflammation is essential to establish immune responses and relies on the development of blood and lymph vessels. Previous work in mice has shown that this process depends on the presence of VEGF-A produced by B cells, macrophages and stromal cells. In humans, however, the cell types and the mechanisms regulating the int...

Key Points Function and maturation of myeloid DCs is abnormal in AP-3 complex-deficient patients. IFN-α secretion in response to HSV-1 is reduced in AP-3–deficient patients.

Dendritic cells (DCs) play a crucial role in the initiation of adaptive immune responses. In addition, through the release of pro- and anti-angiogenic mediators, DCs are key regulators of blood vessel remodeling, a process that characterizes inflammation. Less information is available on the role of DCs in lymphangiogenesis. This study reports that...

Chemokine (CC motif) receptor-like 2 is a 7-transmembrane protein related to the family of the atypical chemokine receptors, which are proteins devoid of chemotactic activity and involved in the control of inflammation. Experimental autoimmune encephalitis is an autoimmune disorder that replicates the inflammatory aspects of multiple sclerosis. Che...

PGE 2 is a lipid mediator abundantly produced in inflamed tissues that exerts relevant immunoregulatory functions. Dendritic cells (DCs) are key players in the onset and shaping of the inflammatory and immune responses and, as such, are well known PGE 2 targets. By contrast, the precise role of human DCs in the production of PGE 2 is poorly charact...

Mesenchymal Stromal Cells (MSC) are multipotent cells currently used for treating several inflammatory disorders thanks to their ability to modulate the immune response. However, the mechanisms by which MSC are able to suppress the immune response have not been fully understood. Chemerin has been recently identified as a chemotactic protein, secret...

Allogeneic haematopoietic-stem-cell transplantation (HSCT) is the treatment of choice for many malignant and non-malignant disorders. However, Graft-versus -Host Disease (GvHD), the major complication of allogeneic HSCT, limits its wider application. Among different sites that can be involved, gastrointestinal GvHD represents the major cause of pat...

The TGF-β superfamily consists of a large group of pleiotropic cytokines that are involved in the regulation of many developmental, physiological and pathological processes. Dendritic cells are antigen-presenting cells that play a key role in innate and adaptive immune responses. Dendritic cells have a complex relationship with the TGF-β cytokine s...

Chemokines are key mediators of inflammation. In pathological tissues, the main roles of chemokines are to regulate leukocyte accumulation through the activation of oriented cell migration and the activation of limited programs of gene transcription. Through these activities, chemokines exert many crucial functions, including the regulation of angi...

Chemokines, and their receptors, are essential regulators of in vivo leukocyte migration and, some years ago, a systematic nomenclature system was developed for the chemokine receptor family. Chemokine receptor biology and biochemistry was recently extensively reviewed (Bachelerie et al., 2014). In this review we also highlighted a new component to...

Adaptor protein-3 (AP-3) is a heterotetrameric complex, which regulates vesicular trafficking. Mutations of the b3A subunit cause the Hermansky–Pudlak syndrome type 2 (HPS-2), a rare genetic disease characterized byalbinism, platelet defects, and recurrent infections. Likewise, pearl mice, which lack functional AP-3, show several HPS-2 defects. The...

Cell migration is a response highly conserved in evolution. Chemotactic factors secreted in injured and inflamed tissues generate a concentration-based, chemotactic gradient that directs leukocytes from the blood compartment into tissue. In this issue of the European Journal of Immunology, Gouwy et al. [Eur. J. Immunol. 2015. 45: XXXX-XXXX] show th...

Although several studies have shown that Mesenchymal Stromal Cells (MSCs) are used for treating inflammatory diseases, the mechanisms underlying their capacity to inhibit the inflammatory response are not understood. Chemerin is an immunoregulatory protein with chemotactic activity, secreted by different cell subsets as a precursor and converted in...

Hypoxia represents an inadequate oxygen supply to tissues, which can modulate cell functions, primarily through the hypoxia-inducible transcription factor HIF-1α. Dendritic cells (DC) are professional antigen-presenting cells and their migration maybe affected by hypoxia, since the local microenvironment in lymphoid organs, as well as in inflamed a...

Oxysterols are involved in maintaining cellular cholesterol levels. Recently, oxysterols have been demonstrated to modulate the function of immune cells and tumor growth. These effects can be dependent on the activation of the oxysterol-binding liver X receptors (LXRs) or, as recently demonstrated for T and B cells, dendritic cells (DCs) and neutro...

Abstract Chronic inflammatory diseases represent a heterogeneous group of conditions that can affect practically any organ or system. An increasing number of biologic agents have been developed to selectively target the cell populations and signaling pathways involved in chronic inflammation, including cytokines, monoclonal antibodies and engineere...

Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking....

Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease characterized by severe joint injury. Recently, research has been focusing on the possible identification of predictor markers of disease onset and/or progression, of joint damage, and of therapeutic response. Recent findings have uncovered the role of white adipose tis...

Chemerin and interleukin (IL)-8 are pro-inflammatory mediators whose role in joint inflammation and cartilage degradation has been demonstrated in in-vitro findings. Studies on their presence in synovial fluid (SF) samples may offer further information on their pathogenic role. The aim of this study was to investigate SF chemerin and IL-8 levels in...

ChemR23 is a chemotactic receptor expressed by APCs, such as dendritic cells, macrophages, and NK cells. Chemerin, the ChemR23 ligand, was detected by immunohistochemistry, to be associated with inflamed endothelial cells in autoimmune diseases, such as lupus erythematosus, psoriasis, and rheumatoid arthritis. This study reports that blood and lymp...

The interaction of NK cells with dendritic cells (DCs) results in reciprocal cell activation through the interaction of membrane proteins and the release of soluble factors. In this article, we report that in NK-DC cocultures, among a set of 84 cytokines investigated, activin A was the second highest induced gene, with CXCL8 being the most upregula...

Chemokines are a family of vertebrate-specific, small-secreted molecules that were originally identified as mediators of leukocyte migration and tissue positioning during the immune response. Subsequently, chemokines were discovered to control movement also of endothelial cells and other cell types in many different contexts. The human chemokine sy...

OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®), a product made of the water soluble fractions of 21 inactivated bacterial strain patterns responsible for respiratory tract infections, is used for the prevention of recurrent upper respiratory tract infections and acute exacerbations in chronic obstructive pulmonary disease pati...

Hermansky Pudlak type 2 syndrome (HPS2) is a rare autosomal recessive primary immune deficiency caused by mutations on β3A gene (AP3B1 gene). The defect results in the impairment of the adaptor protein 3 (AP-3) complex, responsible for protein sorting to secretory lysosomes leading to oculo-cutaneous albinism, bleeding disorders and immunodeficienc...

Dendritic cells (DCs) are potent antigen presenting cells, described as the initiators of adaptive immune responses. Immature monocyte-derived DCs (MDDC) showed decreased CD14 expression, increased cell surface markers DC-SIGN and CD1a and enhanced levels of receptors for the chemokines CCL3 (CCR1/CCR5) and CXCL8 (CXCR1/CXCR2) compared with human C...

OS is a severe combined immunodeficiency characterized by erythrodermia and protracted diarrhea as a result of infiltration of oligoclonal-activated T cells, caused by hypomorphic mutations in RAGs. The RAG2(R229Q) mouse model fully recapitulates the clinical OS phenotype. We evaluated whether T and B cell defects, together with the abnormal lympho...

Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses, thereby facilitating tumor growth. Among immune cells, neutrophils play an important protumorigenic role by favoring neoangiogenesis and/or by suppressing antitumor immune responses. Tumor-derived oxysterols hav...