Macrophages are a diverse set of cells present in all body compartments. This diversity is imprinted by their ontogenetic origin (embryonal versus adult bone marrow-derived cells); the organ context; ...by their activation or deactivation by various signals in the contexts of microbial invasion, tissue damage, and metabolic derangement; and by polarization of adaptive T cell responses. Classic adaptive responses of macrophages include tolerance, priming, and a wide spectrum of activation states, including M1, M2, or M2-like. Moreover, macrophages can retain long-term imprinting of microbial encounters (trained innate immunity). Single-cell analysis of mononuclear phagocytes in health and disease has added a new dimension to our understanding of the diversity of macrophage differentiation and activation. Epigenetic landscapes, transcription factors, and microRNA networks underlie the adaptability of macrophages to different environmental cues. Macrophage plasticity, an essential component of chronic inflammation, and its involvement in diverse human diseases, most notably cancer, is discussed here as a paradigm.
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.
Myeloid‐derived suppressor cells (MDSC) are a heterogeneous population of myelomonocytic cells endowed with suppressive activity. MDSC expand and acquire suppressive functions in chronic inflammatory ...conditions, in particular in neoplastic disorders. As exemplified in two reports in this issue of the European Journal of Immunology, progress has been made in defining MDSC‐inducing signals, MDSC phenotypic diversity and spectrum of action. These recent results provide a basis to better define the relationship of MDSC with the adaptive immune responses of mononuclear phagocytes and neutrophils and to exploit their function in a therapeutic setting.
Summary
Inflammation is an important component of the tumor microenvironment. IL‐1 is an inflammatory cytokine which plays a key role in carcinogenesis and tumor progression. IL‐1 is subject to ...regulation by components of the IL‐1 and IL‐1 receptor (ILR) families. Negative regulators include a decoy receptor (IL‐1R2), receptor antagonists (IL‐1Ra), IL‐1R8, and anti‐inflammatory IL‐37. IL‐1 acts at different levels in tumor initiation and progression, including driving chronic non‐resolving inflammation, tumor angiogenesis, activation of the IL‐17 pathway, induction of myeloid‐derived suppressor cells (MDSC) and macrophage recruitment, invasion and metastasis. Based on initial clinical results, the translation potential of IL‐1 targeting deserves extensive analysis.
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)
As the outbreak of coronavirus disease 2019 (COVID-19) progresses, prognostic markers for early identification of high-risk individuals are an urgent medical need. Italy has one of the highest ...numbers of SARS-CoV-2-related deaths and one of the highest mortality rates. Worldwide, a more severe course of COVID-19 is associated with older age, comorbidities, and male sex. Hence, we searched for possible genetic components of COVID-19 severity among Italians by looking at expression levels and variants in
and
genes, crucial for viral infection.Exome and SNP-array data from a large Italian cohort were used to compare the rare-variants burden and polymorphisms frequency with Europeans and East Asians. Moreover, we looked into gene expression databases to check for sex-unbalanced expression.While we found no significant evidence that
is associated with disease severity/sex bias,
levels and genetic variants proved to be possible candidate disease modulators, prompting for rapid experimental validations on large patient cohorts.
Inflammation is an important component of the tumor microenvironment; however, the mechanisms through which immune cells might promote tumorigenesis are unclear. A recent study indicates that B cells ...and antibodies have a key role in orchestrating macrophage-driven, tumor-promoting inflammation, suggesting that modulating the pathways involved might be of therapeutic benefit in cancers driven by chronic inflammation.
Cancer-related inflammation is a key component of the tumor microenvironment. A report in this issue of
Cancer Cell now indicates that tumor-associated neutrophils in lung cancer can polarize to ...either “N1” or “N2” phenotype that inhibits or promotes cancer development, respectively.
Two studies in this issue of Cell Stem Cell highlight context-dependent roles for MSCs in controlling tumor growth. Lee et al. (2012) show that preactivated MSCs have antitumor effects upon adoptive ...transfer in vivo, and Ren et al. (2012) show that tumor-resident MSCs can promote tumor growth by influencing macrophages.
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