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This Old Neighborhood Made M1 this Way

  • Florian Gruber
    Correspondence
    Correspondence: Florian Gruber, Department of Dermatology, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
    Affiliations
    Department of Dermatology, Medical University of Vienna, Vienna, Austria

    The Christian Doppler Laboratory for Multimodal Analytical Imaging of Aging and Senescence of the Skin (SKINMAGINE), Medical University of Vienna, Vienna, Austria
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  • Mikolaj Ogrodnik
    Affiliations
    Ludwig Boltzmann Research Group Senescence and Healing of Wounds, Vienna, Austria

    Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria

    Austrian Cluster for Tissue Regeneration, Vienna, Austria
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Published:September 29, 2022DOI:https://doi.org/10.1016/j.jid.2022.07.014
      • The numbers of monocyte-derived macrophages (MDMs) are elevated in aged skin.
      • Interaction with senescent fibroblasts elicits a proinflammatory, phagocytic, M1-like phenotype in the MDM.
      • These M1-like macrophages, in return, elicit an extracellular matrix remodeling phenotype in dermal fibroblasts.
      When pttissues age, the composition and the properties of the residing cell populations change, resulting in low-grade inflammation, proteolysis, impaired nutrient sensing, and an increased number of senescent cells (
      • López-Otín C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      ). Although the age-related alterations mentioned earlier seem to occur in most if not all tissues, there are also some age-related changes, which are tissue specific. For example, an accumulation of UV-induced DNA modifications or a decrease in hyaluronic acid synthesis seems to be specific to aging of skin cells and is especially pronounced in dermal fibroblast (
      • Tigges J.
      • Krutmann J.
      • Fritsche E.
      • Haendeler J.
      • Schaal H.
      • Fischer J.W.
      • et al.
      The hallmarks of fibroblast ageing.
      ). Often neglected in their importance for the aging process are changes to the extracellular matrix (ECM). Skin, among other organs, is composed first and foremost of ECM, with cells embedded between the long and elastic fibers of the matrix. Specifically, 70% of skin dry mass can be attributed to the ECM (
      • Zhao X.
      • Psarianos P.
      • Ghoraie L.S.
      • Yip K.
      • Goldstein D.
      • Gilbert R.
      • et al.
      Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis.
      ), including fibers made of collagen, elastin, fibronectin, and proteoglycans, among others, with the cellular fraction providing a much smaller contribution. Despite this disproportion, majority of research omits the aspect of the cell‒ECM interactions and their implications for mammalian physiology and pathology. Although the progressive aging of the environment and ECM of several tissues has been shown to impact the viability and function of cells, the description of aging-related interactions between ECM and skin cells is incomplete. The advent of single-cell and spatial sequencing technologies promotes the detailed tracking of cellular composition and has already brought groundbreaking insights, allowing to determine the dynamics of cellular phenotypes within the skin (
      • Reynolds G.
      • Vegh P.
      • Fletcher J.
      • Poyner E.F.M.
      • Stephenson E.
      • Goh I.
      • et al.
      Developmental cell programs are co-opted in inflammatory skin disease.
      ). In their new article,
      • Gather L.
      • Nath N.
      • Falckenhayn C.
      • Oterino-Sogo S.
      • Bosch T.
      • Wenck H.
      • et al.
      Macrophages are polarized toward an inflammatory phenotype by their aged microenvironment in the human skin.
      analyzed published single-cell sequencing data from the skin of young and old donors, validated them with other published datasets, and identified an age-related increase in the content of monocyte-derived macrophages that display an M1-like proinflammatory and phagocytic phenotype. Furthermore, the in vitro experiments done by
      • Gather L.
      • Nath N.
      • Falckenhayn C.
      • Oterino-Sogo S.
      • Bosch T.
      • Wenck H.
      • et al.
      Macrophages are polarized toward an inflammatory phenotype by their aged microenvironment in the human skin.
      show that the proximity of fibroblasts isolated from aged skin samples prods the neighbor macrophages toward a more proinflammatory phenotype and that this could be enhanced by exposing them to supernatants of senescent fibroblasts. Cytokines that are commonly associated with aging of, infection of, and damage to the skin such as IL-6, CXCL-1, and TNF-α are expressed in significantly higher quantities by macrophages cocultured with aged fibroblasts. Moreover, this inflammatory phenotype of macrophages could further exacerbate this condition by in turn negatively impacting the transcriptional profile of dermal fibroblasts. These in vitro experiments revealed that fibroblasts, which had contact with proinflammatory macrophages, produce more matrix-degrading proteins such as matrix metalloproteinase 2 and fewer ECM components such as procollagen, thereby possibly contributing to the aging-related decline of the ECM.
      These findings provide interesting clues to solve urging open questions on cellular dynamics in skin aging. The foremost of these is on what factors contribute to the age-related decline in the clearance of dermal senescent cells. The failed senescence clearance is observed in tissues presenting chronic inflammation and proteolysis; however how inflammation prevents the elimination of senescent cells is unclear. The results by
      • Gather L.
      • Nath N.
      • Falckenhayn C.
      • Oterino-Sogo S.
      • Bosch T.
      • Wenck H.
      • et al.
      Macrophages are polarized toward an inflammatory phenotype by their aged microenvironment in the human skin.
      indicate that at least in vitro senescent dermal fibroblasts promote an M1 phenotype in the monocyte-derived macrophages and increase their phagocytic capacity. However, whether these changes contribute to the decline of the capacity of the macrophages to eliminate senescent dermal cells needs to be established by functional studies in vivo. It also remains to be determined why skin macrophages change their properties during aging. Are the skin macrophages also undergoing senescence induction and consequently lose the capacity to clear parenchymal senescent cells? Although there is a certain amount of evidence on the senescence-like phenotype of macrophages, for example, of foam cells in atherosclerotic tissue (
      • Childs B.G.
      • Baker D.J.
      • Wijshake T.
      • Conover C.A.
      • Campisi J.
      • van Deursen J.M.
      Senescent intimal foam cells are deleterious at all stages of atherosclerosis.
      ), it is unclear whether this process occurs also in skin macrophages. A potential clue is that lipid mediators, which are produced by senescent dermal fibroblasts, inhibit phagocytosis by monocyte-derived macrophages (
      • Narzt M.S.
      • Pils V.
      • Kremslehner C.
      • Nagelreiter I.M.
      • Schosserer M.
      • Bessonova E.
      • et al.
      Epilipidomics of senescent dermal fibroblasts identify lysophosphatidylcholines as pleiotropic senescence-Associated Secretory phenotype (SASP) factors.
      ).
      Finally, the study by
      • Gather L.
      • Nath N.
      • Falckenhayn C.
      • Oterino-Sogo S.
      • Bosch T.
      • Wenck H.
      • et al.
      Macrophages are polarized toward an inflammatory phenotype by their aged microenvironment in the human skin.
      suggests that age-associated changes in the ECM might arise not only from the internal changes in senescent fibroblasts themselves but also be influenced by inflammatory macrophages. In other words, the age-related change in fibroblasts’ capacity to produce and remodel ECM can be caused by both cell-internal changes of fibroblasts and the inflammation induced in their environment by the M1 macrophages. It is interesting to speculate that this process resembles changes known in wound healing (
      • Ring N.A.R.
      • Valdivieso K.
      • Grillari J.
      • Redl H.
      • Ogrodnik M.
      The role of senescence in cellular plasticity: lessons from regeneration and development and implications for age-related diseases.
      ) and that the inflammation-induced senescence could represent a form of bystander senescence (
      • da Silva P.F.L.
      • Ogrodnik M.
      • Kucheryavenko O.
      • Glibert J.
      • Miwa S.
      • Cameron K.
      • et al.
      The bystander effect contributes to the accumulation of senescent cells in vivo.
      ).
      These and other questions could be potentially addressed by combinations of single-cell and spatial analysis methods. In addition to the spatial assessment of transcriptome, spatial chemical imaging also might address the questions on the interplay between cell types the plasticity of which is increasingly uncovered and the ECM and its structural and chemical modifications in skin aging.

      Conflict of Interest

      The authors state no conflict of interest.

      References

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      Linked Article

      • Macrophages Are Polarized toward an Inflammatory Phenotype by their Aged Microenvironment in the Human Skin
        Journal of Investigative DermatologyVol. 142Issue 12
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          Aging of the skin is accompanied by cellular as well as tissue environmental changes, ultimately reducing the ability of the tissue to regenerate and adequately respond to external stressors. Macrophages are important gatekeepers of tissue homeostasis, and it has been reported that their number and phenotype change during aging in a site-specific manner. How aging affects human skin macrophages and what implications this has for the aging process in the tissue are still not fully understood. Using single-cell RNA-sequencing analysis, we show that there is at least a 50% increase of macrophages in human aged skin, which appear to have developed from monocytes and exhibit more proinflammatory M1-like characteristics.
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