Crosstalk Between Innate and T Cell Adaptive Immunity With(in) the Muscle

Bonomo, Adriana; Pinto‐Mariz, Fernanda; Riederer, Ingo; Benjamim, Cláudia F.; Butler‐Browne, Gillian; Mouly, Vincent; Savino, Wilson

doi:10.3389/fphys.2020.573347

Cited by 20 publications

(26 citation statements)

References 119 publications

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“…In parallel, notable efforts were performed to identify muscle-resident and other nonmuscular cells whose abilities were to be expanded in vitro; to migrate efficiently from the site of injection into dystrophic muscles; to develop into muscle and contribute to muscular regeneration. Different subpopulations were studied (muscle-derived stem cells; mesoangioblasts; CD133+ cells; mesenchymal stem cells) [6,7], but none of them were able to rescue efficaciously DMD phenotype, partly due to unresolved inflammatory responses that dramatically limited their migratory and differentiative potential [8].…”

Section: Introductionmentioning

confidence: 99%

The Immune System in Duchenne Muscular Dystrophy Pathogenesis

et al. 2021

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Growing evidence demonstrates the crosstalk between the immune system and the skeletal muscle in inflammatory muscle diseases and dystrophic conditions such as Duchenne Muscular Dystrophy (DMD), as well as during normal muscle regeneration. The rising of inflammation and the consequent activation of the immune system are hallmarks of DMD: several efforts identified the immune cells that invade skeletal muscle as CD4+ and CD8+ T cells, Tregs, macrophages, eosinophils and natural killer T cells. The severity of muscle injury and inflammation dictates the impairment of muscle regeneration and the successive replacement of myofibers with connective and adipose tissue. Since immune system activation was traditionally considered as a consequence of muscular wasting, we recently demonstrated a defect in central tolerance caused by thymus alteration and the presence of autoreactive T-lymphocytes in DMD. Although the study of innate and adaptive immune responses and their complex relationship in DMD attracted the interest of many researchers in the last years, the results are so far barely exhaustive and sometimes contradictory. In this review, we describe the most recent improvements in the knowledge of immune system involvement in DMD pathogenesis, leading to new opportunities from a clinical point-of-view.

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Section: Introductionmentioning

confidence: 99%

The Immune System in Duchenne Muscular Dystrophy Pathogenesis

et al. 2021

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“…Between the myeloid and the lymphoid immune cell repertoire, the myeloid cells are the primary responders to the inflammatory cues in tissues that eventually prime the adaptive immune response (41)(42)(43). The adaptive system further directs myeloid cell function and in turn, dictate disease outcome (44)(45)(46). While several studies have focused on understanding the role of lymphoid cells in exacerbating inflammatory disease conditions, much less is understood about the earliest interactions between the myeloid and the niche cells that initiate these inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Epithelial-Macrophage Crosstalk Initiates Sterile Inflammation in Embryonic Skin

et al. 2021

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Macrophages are highly responsive to the environmental cues and are the primary responders to tissue stress and damage. While much is known about the role of macrophages during inflammatory disease progression; the initial series of events that set up the inflammation remains less understood. In this study, we use next generation sequencing (NGS) of embryonic skin macrophages and the niche cells - skin epithelia and stroma in the epidermis specific knockout of integrin beta 1 (Itgβ1) model to uncover specific roles of each cell type and identify how these cell types communicate to initiate the sterile inflammatory response. We demonstrate that while the embryonic skin fibroblasts in the Itgβ1 knockout skin are relatively inactive, the keratinocytes and macrophages are the critical responders to the sterile inflammatory cues. The epidermis expresses damage associated molecular patterns (DAMPs), stress response genes, pro-inflammatory cytokines, and chemokines that aid in eliciting the inflammatory response. The macrophages, in-turn, respond by acquiring enhanced M2-like characteristics expressing ECM remodeling and matrisome signatures that exacerbate the basement membrane disruption. Depletion of macrophages by blocking the CSF1 receptor (CSF1R) results in improved basement membrane integrity and reduced ECM remodeling activity in the KO skin. Further, blocking the skin inflammation with celecoxib reveals that the acquired fate of macrophages in the KO skin is dependent on its interaction with the epidermal compartment through COX2 dependent cytokine production. Taken together, our study highlights a critical crosstalk between the epithelia and the dermal macrophages that shapes macrophage fate and initiates sterile inflammation in the skin. The insights gained from our study can be extrapolated to other inflammatory disorders to understand the early events that set up the disease.

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“…Chronic cycles of muscle tissue damage and fibre repair are triggered by dystrophin deficiency and cause a sustained immune response, which results in a chronic inflammatory phenotype of dystrophinopathy [280,314,315]. The innate immune response is accompanied by high levels of macrophage activity and the release of a variety of signalling factors, as well as the recruitment of myofibroblasts [31]. The potential interplay between chronic inflammation and myofibrosis in damaged fibres, as well as the role of abnormal Ca 2+ -handling in dystrophin-deficient fibres, is summarised in Fig.…”

Section: Reactive Myofibrosis and Chronic Inflammation As Key Symptoms Of Dystrophinopathymentioning

confidence: 99%

“…The inflammatory phenotype of progressive skeletal muscle degeneration due to dystrophin deficiency is associated with a variety of cellular immune responses [ 280 ], especially interference by the innate immune system [ 31 ] but also acquired immune responses [ 314 ]. As already discussed above, there appears to be a close link between chronic inflammation and reactive myofibrosis in X-linked muscular dystrophy [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the shedding of peptides, protein fragments or proteins through the leaky muscle plasmalemma presents these muscle components as potential neoantigens to the adaptive immune system [ 341 ]. Importantly, a large number of signalling cytokines and chemokines promote the infiltration of dystrophic fibres by neutrophiles, macrophages and dendritic cell populations [ 31 , 319 ].…”

Section: Introductionmentioning

confidence: 99%

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Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

Ohlendieck

Swandulla

2021

Pflugers Arch - Eur J Physiol

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Duchenne muscular dystrophy is a highly progressive muscle wasting disorder due to primary abnormalities in one of the largest genes in the human genome, the DMD gene, which encodes various tissue-specific isoforms of the protein dystrophin. Although dystrophinopathies are classified as primary neuromuscular disorders, the body-wide abnormalities that are associated with this disorder and the occurrence of organ crosstalk suggest that a multi-systems pathophysiological view should be taken for a better overall understanding of the complex aetiology of X-linked muscular dystrophy. This article reviews the molecular and cellular effects of deficiency in dystrophin isoforms in relation to voluntary striated muscles, the cardio-respiratory system, the kidney, the liver, the gastrointestinal tract, the nervous system and the immune system. Based on the establishment of comprehensive biomarker signatures of X-linked muscular dystrophy using large-scale screening of both patient specimens and genetic animal models, this article also discusses the potential usefulness of novel disease markers for more inclusive approaches to differential diagnosis, prognosis and therapy monitoring that also take into account multi-systems aspects of dystrophinopathy. Current therapeutic approaches to combat muscular dystrophy are summarised.

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Crosstalk Between Innate and T Cell Adaptive Immunity With(in) the Muscle

Cited by 20 publications

References 119 publications

The Immune System in Duchenne Muscular Dystrophy Pathogenesis

The Immune System in Duchenne Muscular Dystrophy Pathogenesis

Epithelial-Macrophage Crosstalk Initiates Sterile Inflammation in Embryonic Skin

Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

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