Myeloid cell diversification during regenerative inflammation: Lessons from skeletal muscle

Patsalos, Andreas; Tzerpos, Petros; Wei, Xiaoyan; Nagy, László

doi:10.1016/j.semcdb.2021.05.005

Cited by 9 publications

(13 citation statements)

References 138 publications

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“…Future studies could use functional as well as a cytometry by time of flight dataset composed of several markers to provide an orthogonal validation of MF subtypes and their surface receptor expression variability during the time course of regeneration. Trajectory analysis could also allow parsing the MF differentiation and subtype specification after injury in distinct states like anti-inflammatory/resolution–related, growth factor–secreting, pro-inflammatory, and antigen-presenting, with diverse gene expression signatures, as recently hypothesized ( Patsalos et al, 2021 ).…”

Section: Discussionmentioning

confidence: 94%

“…To provide an unbiased and robust foundation for our study, we systematically profiled the in situ differentiation of circulating blood monocytes to inflammatory Ly6C high and then to repair-Ly6C low MFs during sterile inflammation and muscle regeneration with the goal of identifying distinct transcriptional patterns across these two transitions ( Fig. 1 A ; reviewed recently by Chazaud, 2020 ; Patsalos et al, 2021 ). In this model, sterile inflammation is caused by a single intramuscular CTX injection, which in turn triggers severe muscle fiber death.…”

Section: Resultsmentioning

confidence: 99%

“…To our knowledge, this is the first time circulating monocyte profiling, and multiple time points using the most inclusive MF gating strategy, are taken into consideration simultaneously for a more comprehensive analysis of the MF phenotypic and functional state continuum. There is also strong evidence that the indicated time points we selected reflect all phases of regeneration (pro-inflammatory, resolution, and repair phases) and at the same time provide sufficient cell numbers to perform the RNA-seq immune profiling ( Giannakis et al, 2019 ; Patsalos et al, 2021 ). The aforementioned switches in MF phenotype have been documented by multiple transcriptomic, epigenomic, lineage tracing, and lipidomic approaches by several laboratories, including ours ( Perdiguero et al, 2011 ; Mounier et al, 2013 ; Varga et al, 2013 ; Wang et al, 2014 ; Tonkin et al, 2015 ; Varga et al, 2016a ; Panduro et al, 2018 ; Giannakis et al, 2019 ; Patsalos et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

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A growth factor–expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15

Patsalos

Halász

Medina-Serpas

et al. 2021

Journal of Experimental Medicine

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Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte–derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage–derived factors coordinate tissue repair. Gene expression kinetics–based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration–associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor–expressing macrophages [GFEMs]).

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A growth factor–expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15

Patsalos

Halász

Medina-Serpas

et al. 2021

Journal of Experimental Medicine

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“…Notably, muscle and kidney, together with liver and lung, are parenchymal tissues. These tissue types undergo a similar poor organ regeneration ability, because of evolutionary trade-offs, which are especially related to balancing effects between the immune system and the shape of physiological and pathological processes [ 42 ]. Additionally, a similar high CU value clustering is even more evident for some muscle (COL6A1, RPL3L, MYLPF, TMEM38A, TNNC2, LMNA, DES, LBX1, SGCA, ANKRD23, CAPN3, DYSF, ACTN3) and kidney (UMOD, BSND, SLC22A8, MIOX, AQP6, PKD1, SLC12A3, GGACT) genes, underlining some gene-specific and/or organ related functions.…”

Section: Discussionmentioning

confidence: 99%

Calculating and comparing codon usage values in rare disease genes highlights codon clustering with disease-and tissue- specific hierarchy

et al. 2022

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We designed a novel strategy to define codon usage bias (CUB) in 6 specific small cohorts of human genes. We calculated codon usage (CU) values in 29 non-disease-causing (NDC) and 31 disease-causing (DC) human genes which are highly expressed in 3 distinct tissues, kidney, muscle, and skin. We applied our strategy to the same selected genes annotated in 15 mammalian species. We obtained CUB hierarchical clusters for each gene cohort which showed tissue-specific and disease-specific CUB fingerprints. We showed that DC genes (especially those expressed in muscle) display a low CUB, well recognizable in codon hierarchical clustering. We defined the extremely biased codons as “zero codons” and found that their number is significantly higher in all DC genes, all tissues, and that this trend is conserved across mammals. Based on this calculation in different gene cohorts, we identified 5 codons which are more differentially used across genes and mammals, underlining that some genes have favorite synonymous codons in use. Since of the muscle genes clear clusters, and, among these, dystrophin gene surprisingly does not show any “zero codon” we adopted a novel approach to study CUB, we called “mapping-on-codons”. We positioned 2828 dystrophin missense and nonsense pathogenic variations on their respective codon, highlighting that its frequency and occurrence is not dependent on the CU values. We conclude our strategy consents to identify a hierarchical clustering of CU values in a gene cohort-specific fingerprints, with recognizable trend across mammals. In DC muscle genes also a disease-related fingerprint can be observed, allowing discrimination between DC and NDC genes. We propose that using our strategy which studies CU in specific gene cohorts, as rare disease genes, and tissue specific genes, may provide novel information about the CUB role in human and medical genetics, with implications on synonymous variations interpretation and codon optimization algorithms.

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“…However, these processes are late events responsible for the replacement of lost tissue. Prior to renewal, immune cells carry out functions essential for proper tissue repair, such as clearance of the injured area [ 9 ] and a subsequent inflammation, termed, regenerative inflammation [ 10 – 12 ]. Regenerative inflammation is associated with an immunosuppressive and pro-regenerative response generated by monocyte-derived macrophages that promote tissue repair.…”

Section: The Crosstalk Between Inflammation and Regenerationmentioning

confidence: 99%

Regenerative inflammation: When immune cells help to re‐build tissues

2022

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Inflammation is an essential immune response critical for responding to infection, injury and maintenance of tissue homeostasis. Upon injury, regenerative inflammation promotes tissue repair by a timed and coordinated infiltration of diverse cell types and the secretion of growth factors, cytokines and lipids mediators. Remarkably, throughout evolution as well as mammalian development, this type of physiological inflammation is highly associated with immunosuppression. For instance, regenerative inflammation is the consequence of an in situ macrophage polarization resulting in a transition from pro‐inflammatory to anti‐inflammatory/pro‐regenerative response. Immune cells are the first responders upon injury, infiltrating the damaged tissue and initiating a pro‐inflammatory response depleting cell debris and necrotic cells. After phagocytosis, macrophages undergo multiple coordinated metabolic and transcriptional changes allowing the transition and dictating the initiation of the regenerative phase. Differences between a highly efficient, complete ad integrum tissue repair, such as, acute skeletal muscle injury, and insufficient regenerative inflammation, as the one developing in Duchenne Muscular Dystrophy (DMD), highlight the importance of a coordinated response orchestrated by immune cells. During regenerative inflammation, these cells interact with others and alter the niche, affecting the character of inflammation itself and, therefore, the progression of tissue repair. Comparing acute muscle injury and chronic inflammation in DMD, we review how the same cells and molecules in different numbers, concentration and timing contribute to very different outcomes. Thus, it is important to understand and identify the distinct functions and secreted molecules of macrophages, and potentially other immune cells, during tissue repair, and the contributors to the macrophage switch leveraging this knowledge in treating diseases.

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Myeloid cell diversification during regenerative inflammation: Lessons from skeletal muscle

Cited by 9 publications

References 138 publications

A growth factor–expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15

A growth factor–expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15

Calculating and comparing codon usage values in rare disease genes highlights codon clustering with disease-and tissue- specific hierarchy

Regenerative inflammation: When immune cells help to re‐build tissues

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