Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS

Trías, Emiliano; King, Peter H.; Si, Ying; Kwon, Yuri; Varela, Valentina; Ibarburu, Sofía; Kovacs, Mariángeles; Moura, Ivan C.; Beckman, Joseph S.; Hermine, Olivier

doi:10.1172/jci.insight.123249

Cited by 103 publications

(93 citation statements)

References 60 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As described previously (Trias et al, , ), only transgenic rats showing weakness and gait alterations in hind limbs as the first clinical sign were selected for masitinib treatment studies. Male rats were divided randomly into the masitinib or vehicle‐treated groups.…”

Section: Methodsmentioning

confidence: 99%

“…Mast cells are also recruited (Esposito, De Santis, Monteforte, & Baccari, ), orchestrating complex vascular and immune cell responses, including the chemoattraction of phagocytic neutrophils that further contribute to myelin clearance (Lindborg et al, ). In comparison, ALS nerve pathology similarly involves reactive changes in SCs (Keller, Gravel, & Kriz, ) as well as the recruitment of monocytes, macrophages, mast cells, and neutrophils (Chiu et al, ; Trias et al, ; Van Dyke et al, ).Such immune cell infiltration of the peripheral motor pathways in ALS has been linked to both protective and deleterious effects on motor neuron degeneration and disease progression (Nardo et al, ). However, the functional link between SCs and immune cell influx to degenerating peripheral nerves in ALS remains unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Of therapeutic interest in ALS, it has been demonstrated that downregulation of inflammation by tyrosine kinase inhibitor drugs such as GW2580 or masitinib is associated with decreased spinal nerve pathology and NMJ denervation, and prolonged survival in rodent models of ALS (Martinez‐Muriana et al, ; Trias et al, ; Trias et al, ). In particular, masitinib has successfully completed a randomized, controlled, phase 2/3 trial in ALS patients, showing a significant and clinically meaningful benefit for masitinib over placebo in relevant measures of disease progression (Mora et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…CSF‐1R and c‐Kit are typically expressed in myeloid cells and mast cells, respectively (Galli, Tsai, & Wershil, ; Stanley & Chitu, ). In SOD1 G93A rats developing paralysis, masitinib downregulates mast cells and neutrophil infiltration in both the sciatic nerve and skeletal muscle motor nerve terminals (Trias et al, ; Trias et al, ). In addition, masitinib decreases CSF‐1R‐dependent microgliosis in the lumbar spinal cord, suggesting a multitarget and multifaceted effect involving various inflammatory pathways in the central and peripheral nervous systems (Trias et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…SCF/c‐Kit signaling drives chemoattraction of mast cell precursors, their differentiation into mature mast cells and ultimate degranulation, with the release of inflammatory and vasoactive molecules (Galli et al, ). Mast cells are key in orchestrating chronic inflammation and immune cell infiltration (Metz et al, ) and recently have been reported to extensively infiltrate the muscle and sciatic nerve of ALS patients and SOD1 G93A rats (Trias et al, ; Trias et al, ). The cellular sources of CSF1, IL‐34, and SCF in ALS peripheral nerves remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

Trías

Kovacs

King

et al. 2019

Glia

Self Cite

View full text Add to dashboard Cite

Distal axonopathy is a recognized pathological feature of amyotrophic lateral sclerosis (ALS). In the peripheral nerves of ALS patients, motor axon loss elicits a Wallerian‐like degeneration characterized by denervated Schwann cells (SCs) together with immune cell infiltration. However, the pathogenic significance of denervated SCs accumulating following impaired axonal growth in ALS remains unclear. Here, we analyze SC phenotypes in sciatic nerves of ALS patients and paralytic SOD1G93A rats, and identify remarkably similar and specific reactive SC phenotypes based on the pattern of S100β, GFAP, isolectin and/or p75NTR immunoreactivity. Different subsets of reactive SCs expressed colony‐stimulating factor‐1 (CSF1) and Interleukin‐34 (IL‐34) and closely interacted with numerous endoneurial CSF‐1R‐expressing monocyte/macrophages, suggesting a paracrine mechanism of myeloid cell expansion and activation. SCs bearing phagocytic phenotypes as well as endoneurial macrophages expressed stem cell factor (SCF), a trophic factor that attracts and activates mast cells through the c‐Kit receptor. Notably, a subpopulation of Ki67+ SCs expressed c‐Kit in the sciatic nerves of SOD1G93A rats, suggesting a signaling pathway that fuels SC proliferation in ALS. c‐Kit+ mast cells were also abundant in the sciatic nerve from ALS donors but not in controls. Pharmacological inhibition of CSF‐1R and c‐Kit with masitinib in SOD1G93A rats potently reduced SC reactivity and immune cell infiltration in the sciatic nerve and ventral roots, suggesting a mechanism by which the drug ameliorates peripheral nerve pathology. These findings provide strong evidence for a previously unknown inflammatory mechanism triggered by SCs in ALS peripheral nerves that has broad application in developing novel therapies.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

Trías

Kovacs

King

et al. 2019

Glia

Self Cite

View full text Add to dashboard Cite

show abstract

Effect of lncRNA H19 on nerve degeneration and regeneration after sciatic nerve injury in rats

Cai

Feng

et al. 2021

Developmental Neurobiology

View full text Add to dashboard Cite

Hundreds of millions of people worldwide suffer from peripheral nerve damage resulting from car accidents, falls, industrial accidents, residential accidents, and wars. The purpose of our study was to further investigate the effects of Wallerian degeneration (WD) after rat sciatic nerve injury and to screen for critical long noncoding RNAs (lncRNAs) in WD. We found H19 to be essential for nerve degeneration and regeneration and to be highly expressed in the sciatic nerves of rats with WD. lncRNA H19 potentially impaired the recovery of sciatic nerve function in rats. H19 was mainly localized in the cytoplasm of Schwann cells (SCs) and promoted their migration. H19 promoted the apoptosis of dorsal root ganglion (DRG) neurons and slowed the growth of DRG axons. The lncRNA H19 may play a role in WD through the Wnt/β‐catenin signaling pathway and is coexpressed with a variety of crucial mRNAs during WD. These data provide further insight into the molecular mechanisms of WD.

show abstract

Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia

Widner

Zhao

et al. 2021

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

Background Eighty per cent of United States advanced cancer patients faces a worsened prognosis due to cancer‐associated cachexia. Inflammation is one driver of muscle atrophy in cachexia, and skeletal muscle‐resident immune cells could be a source of inflammation. This study explores the efficacy of cancer activated skeletal muscle‐resident mast cells as a biomarker and mediator of cachexia. Methods Individual gene markers for immune cells were assessed in a publicly available colon carcinoma cohort of normal (n = 3), moderate cachexia (n = 3), and severe cachexia (n = 4) mice. Lewis lung carcinoma (LL/2) cells induced cachexia in C57BL/6 mice, and a combination of toluidine blue staining, immunofluorescence, quantitative polymerase chain reaction, and western blots measured innate immune cell expression in hind limb muscles. In vitro measurements included C2C12 myotube diameter before and after treatment with media from primary murine mast cells activated with LL/2 conditioned media. To assess translational potential in human samples, innate immune cell signatures were assessed for correlation with skeletal muscle atrophy and apoptosis, dietary excess, and cachexia signatures in normal skeletal muscle tissue. Gene set enrichment analysis was performed with innate immune cell signatures in publicly available cohorts for upper gastrointestinal (GI) cancer and pancreatic ductal adenocarcinoma (PDAC) patients (accession: GSE34111 and GSE130563, respectively). Results Individual innate immunity genes (TPSAB1 and CD68) showed significant increases in severe cachexia (weight loss > 15%) mice in a C26 cohort (GSE24112). Induction of cachexia in C57BL/6 mice with LL/2 subcutaneous injection significantly increased the number of activated skeletal muscle‐resident degranulating mast cells. Murine mast cells activated with LL/2 conditioned media decreased C2C12 myotube diameter (P ≤ 0.05). Normal human skeletal muscle showed significant positive correlations between innate immune cell signatures and muscle apoptosis and atrophy, dietary excess, and cachexia signatures. The mast cell signature was up‐regulated (positive normalized enrichment score and false discovery rate ≤ 0.1) in upper GI cachectic patients (n = 12) compared with control (n = 6), as well as in cachectic PDAC patients (n = 17) compared with control patients (n = 16). Conclusions Activated skeletal muscle‐resident mast cells are enriched in cachectic muscles, suggesting skeletal‐muscle resident mast cells may serve as a biomarker and mediator for cachexia development to improve patient diagnosis and prognosis.

show abstract

Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS

Cited by 103 publications

References 60 publications

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

Effect of lncRNA H19 on nerve degeneration and regeneration after sciatic nerve injury in rats

Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia

Contact Info

Product

Resources

About