Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or ...M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.
Resident and recruited macrophages are key players in the homeostatic function of the liver and in its response to tissue damage. In response to environmental signals, macrophages undergo polarized ...activation to M1 or M2 or M2‐like activation states. These are extremes of a spectrum in a universe of activation states. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of mononuclear phagocytes. Resident and recruited macrophages are a key component of diverse homeostatic and pathological responses of hepatic tissue. Polarized macrophages interact with hepatic progenitor cells, integrate metabolic adaptation, mediate responses to infectious agents, orchestrate fibrosis in a yin‐yang interaction with hepatic stellate cells, and are a key component of tumor‐promoting inflammation. Conclusion: A better understanding of macrophage diversity and plasticity in liver homeostasis and pathology may pave the way to innovative diagnostic and therapeutic approaches. (Hepatology 2014;59:2034–2042)
Immune checkpoints are inhibitory receptor/ligand pairs regulating immunity that are exploited as key targets of anti-cancer therapy. Although the PD-1/PD-L1 pair is one of the most studied immune ...checkpoints, several aspects of its biology remain to be clarified. It has been established that PD-1 is an inhibitory receptor up-regulated by activated T, B, and NK lymphocytes and that its ligand PD-L1 mediates a negative feedback of lymphocyte activation, contributing to the restoration of the steady state condition after acute immune responses. This loop might become detrimental in the presence of either a chronic infection or a growing tumor. PD-L1 expression in tumors is currently used as a biomarker to orient therapeutic decisions; nevertheless, our knowledge about the regulation of PD-L1 expression is limited. The present review discusses how NF-κB, a master transcription factor of inflammation and immunity, is emerging as a key positive regulator of PD-L1 expression in cancer. NF-κB directly induces
gene transcription by binding to its promoter, and it can also regulate PD-L1 post-transcriptionally through indirect pathways. These processes, which under conditions of cellular stress and acute inflammation drive tissue homeostasis and promote tissue healing, are largely dysregulated in tumors. Up-regulation of PD-L1 in cancer cells is controlled via NF-κB downstream of several signals, including oncogene- and stress-induced pathways, inflammatory cytokines, and chemotherapeutic drugs. Notably, a shared signaling pathway in epithelial cancers induces both PD-L1 expression and epithelial-mesenchymal transition, suggesting that PD-L1 is part of the tissue remodeling program. Furthermore, PD-L1 expression by tumor infiltrating myeloid cells can contribute to the immune suppressive features of the tumor environment. A better understanding of the interplay between NF-κB signaling and PD-L1 expression is highly relevant to cancer biology and therapy.
Innate immunity has an adaptive component, which has been referred to as "memory," "trained," "imprinted" or "adaptive." Plasticity is a hallmark of cells of the monocyte-macrophage lineage. ...Microbial recognition and cytokines profoundly affect macrophage function causing a range of adaptive responses including activation, priming, or tolerance. These adaptive responses of macrophages include production of humoral fluid-phase pattern recognition molecules such as the prototypic long pentraxin PTX3. These components of humoral innate immunity in turn cooperate with and regulate phagocyte function. Progress has been made in defining the molecular basis underlying the polarized activation of macrophages, including signaling mediators, transcription factors, epigenetic modifications, and the microRNA network. The definition of molecules and mechanisms associated with plasticity and polarized activation of macrophages may provide a basis for innovative diagnostic and therapeutic approaches.
An intrinsic (oncogene-driven) pathway and an extrinsic (microenvironment-driven) pathway connect inflammatory reactions and cancer. M2-polarized tumor-associated macrophages and the related ...myeloid-derived suppressor cells are key prototypic components of smoldering inflammation driving neoplastic progression. However, mononuclear phagocytes can exert anti-tumor activity by killing tumor cells and eliciting tissue disruptive reactions (M1), a likely scenario in the early phases of carcinogenesis of immunogenic tumors and following therapeutic intervention. Shifting the macrophage balance represents a viable therapeutic target. Herein, the 'macrophage balance' is discussed in the context of the apparent paradox of tumor promotion by innate immunity-driven inflammation and the seemingly opposed tumor surveillance by adaptive immune responses.
Abstract Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. In the tumor microenvironment neoplastic cells shape the differentiation and functional ...orientation of TAM which, in turn, express several protumoral functions, including secretion of growth factors and matrix-proteases, promotion of angiogenesis and suppression of adaptive immunity. This review analyzes our current knowledge of TAM and their involvement in tumor development and progression. The interplay between TAM and neoplastic cells represents a promising target of future therapeutic approaches.
Cancer progression generates a chronic inflammatory state that dramatically influences hematopoiesis, originating different subsets of immune cells that can exert pro- or anti-tumor roles. Commitment ...towards one of these opposing phenotypes is driven by inflammatory and metabolic stimuli derived from the tumor-microenvironment (TME). Current immunotherapy protocols are based on the reprogramming of both specific and innate immune responses, in order to boost the intrinsic anti-tumoral activity of both compartments. Growing pre-clinical and clinical evidence highlights the key role of metabolism as a major influence on both immune and clinical responses of cancer patients. Indeed, nutrient competition (i.e., amino acids, glucose, fatty acids) between proliferating cancer cells and immune cells, together with inflammatory mediators, drastically affect the functionality of innate and adaptive immune cells, as well as their functional cross-talk. This review discusses new advances on the complex interplay between cancer-related inflammation, myeloid cell differentiation and lipid metabolism, highlighting the therapeutic potential of metabolic interventions as modulators of anticancer immune responses and catalysts of anticancer immunotherapy.
Frailty in Rheumatic Diseases Motta, Francesca; Sica, Antonio; Selmi, Carlo
Frontiers in immunology,
10/2020, Volume:
11
Journal Article
Peer reviewed
Open access
Frailty is a syndrome characterized by the decline in the physiologic reserve and function of several systems, leading to increased vulnerability and adverse health outcomes. While common in the ...elderly, recent studies have underlined the higher prevalence of frailty in chronic diseases, independent of age. The pathophysiological mechanisms that contribute to frailty have not been completely understood, although significant progresses have recently been made. In this context, chronic inflammation is likely to play a pivotal role, both directly and indirectly through other systems, such as the musculoskeletal, endocrine, and neurological systems. Rheumatic diseases are characterized by chronic inflammation and accumulation of deficits during time. Therefore, studies have recently started to explore the link between frailty and rheumatic diseases, and in this review, we report what has been described so far. Frailty is dynamic and potentially reversible with 8.3%-17.9% of older adults spontaneously improving their frailty status over time. Muscle strength is likely the most significant influencing factor which could be improved with training thus pointing at the need to maintain physical activity. Not surprisingly, frailty is more prevalent in patients affected by rheumatic diseases than in healthy controls, regardless of age and is associated with high disease activity to affect the clinical outcomes, largely due to chronic inflammation. More importantly, the treatment of the underlying condition may prevent frailty. Scales to assess frailty in patients affected by rheumatic diseases have been proposed, but larger casuistries are needed to validate disease-specific indexes, which could allow more accurate prognostic estimates than demographic and disease-related variables alone. Frail patients can be more vulnerable and more difficult to treat, due to the risk of side effects, therefore frailty should be taken into account in clinical decisions. Clinical trials addressing frailty could identify patients who are less likely to tolerate potentially toxic medications and might benefit from more conservative regimens. In conclusion, the implementation of the concept of frailty in rheumatology will allow a better understanding of the patient global health, a finest risk stratification and a more individualized management strategy.
Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions ...of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.
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