ADAM17-deficiency on microglia but not on macrophages promotes phagocytosis and functional recovery after spinal cord injury

Sommer, Daniela; Corstjens, Inge; Sanchez, Selien; Dooley, Dearbhaile; Lemmens, Stefanie; Broeckhoven, Jana Van; Bogie, Jeroen F. J.; Vanmierlo, Tim; Vidal, Pía M.; Rose–John, Stefan; Gou-Fàbregas, Myriam; Hendrix, Sven

doi:10.1016/j.bbi.2019.02.032

Cited by 27 publications

(30 citation statements)

References 60 publications

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“…This was associated with increased uptake of apoptotic neuronal cells by microglia and increased CD36 expression on microglia. [30]. However, in our study we could not observe an increase in the CD36 level on the cell surface of monocytic cells after ADAM17 knockdown.…”

Section: Discussioncontrasting

confidence: 87%

“…In the case of ADAM17 inhibition, however, side effects must be expected due to the involvement of the protease in a large number of signalling pathways. As mentioned before, ADAM17 inhibition or knockout improved the uptake of apoptotic cells by microglia after spinal cord injury in mice [30]. Whether treatment with an ADAM17 inhibitor would also improve bacterial uptake by either microglial cells or potentially also by peripheral phagocytes and thereby improved antibacterial defence needs to be further studied in murine models of infection.…”

Section: Discussionmentioning

confidence: 87%

“…Moreover, for each cellular function during the immune response, the importance of the different proteases can vary considerably. A recent study showed that ADAM17-deficiency in microglia leads to higher uptake of apoptotic cells [30], but implications for antibacterial defense were not investigated To our knowledge, a direct role of the proteases in bacterial uptake via isolated leukocytes has not yet been described.…”

Section: Introductionmentioning

confidence: 96%

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The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

Seifert

Wozniak

Düsterhöft

et al. 2020

IJMS

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Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics.

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Section: Discussioncontrasting

confidence: 87%

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 96%

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The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

Seifert

Wozniak

Düsterhöft

et al. 2020

IJMS

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“…ADAM17 plays a negative role in nerve regeneration. Both the ADAM17 hypomorphic mouse (ADAM17 Ex/Ex ) and a mouse model with deletion of ADAM17 in microglia displayed a better functional recovery after spinal cord injury (SCI) [148]. This phenotype, which was not reproduced by deletion of ADAM17 in endothelial cells or macrophages, was characterized by higher clearance of apoptotic cells and augmented axon growth, potentially due to higher levels of the phagocytic receptor CD36, which is upregulated in ADAM17-deficient mice.…”

Section: Nerve Recoverymentioning

confidence: 99%

Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

et al. 2021

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For decades, disintegrin and metalloproteinase 17 (ADAM17) has been the object of deep investigation. Since its discovery as the tumor necrosis factor convertase, it has been considered a major drug target, especially in the context of inflammatory diseases and cancer. Nevertheless, the development of drugs targeting ADAM17 has been harder than expected. This has generally been due to its multifunctionality, with over 80 different transmembrane proteins other than tumor necrosis factor α (TNF) being released by ADAM17, and its structural similarity to other metalloproteinases. This review provides an overview of the different roles of ADAM17 in disease and the effects of its ablation in a number of in vivo models of pathological conditions. Furthermore, here, we comprehensively encompass the approaches that have been developed to accomplish ADAM17 selective inhibition, from the newest non-zinc-binding ADAM17 synthetic inhibitors to the exploitation of iRhom2 to specifically target ADAM17 in immune cells.

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“…ADAM17 can promote the survival of microglia through the EGFR pathway after spinal cord injury. [24,25] Inhibition of ADAM17 after cortical injury can reduce gliosis at the site of injury by promoting neuron formation as well as nerve repair. [24,26] The results of these studies suggest that ADAM17 plays an important role in nerve repair.…”

Section: Introductionmentioning

confidence: 99%

ADAM17 Aggravates the Inflammatory Response by Modulating Microglia Polarization Through the TGF-β1/Smad Pathway Following Experimental Traumatic Brain Injury

chen

Zeng

Wang

et al. 2021

Preprint

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BackgroundMicroglia-mediated neuroinflammatory responses play important roles in secondary neurological injury after traumatic brain injury (TBI). The TGF-β pathway participates in the regulation of M1/M2 phenotype transformation of microglia. TGF-β can activate the Smad pathway by binding to TGF-βRs, which is regulated by the cleavage function of A disintegrin and metalloproteinase 17 (ADAM17). ADAM17, as an important regulatory factor of the TGF-β pathway, is considered an important factor in regulating the inflammatory response. However, the role of ADAM17 and the associated signaling pathways in the pathological process after TBI remain unclear.MethodsA rat model of TBI was established by the Feeney weight-drop method. Neurological severity, brain water content, and Nissl staining were used to evaluate the neuroprotective effect of inhibiting ADAM17 expression. In vitro and in vivo experiments were conducted to detect the transformation of microglia M1/M2 phenotype polarization and the neuroinflammatory response after specific inhibition of ADAM17. The formation of TGF-βRs and TGF-β1/TGF-βRII complexes on microglia were detected by immunofluorescence, western blot analysis, and co-immunoprecipitation in order to evaluate the effect of ADAM17 inhibition on the TGF-β1/Smad pathway. Meanwhile, Smad nuclear translocation, secretion, and TGF-β1/ Smad-mediated activation of the inflammatory reaction were referenced to evaluate the effects of ADAM17 inhibition and gain further insight into the mechanisms underlying development of the neuroendocrine response after TBI.ResultsADAM17 was highly expressed after TBI and mainly located in the microglia. Specific inhibition of ADAM17 reduced permeability of the blood-brain barrier, the degree of brain edema, and apoptosis of nerve cells, and improved neurological function after TBI. Further studies indicated that the neuroprotective effect of ADAM17 inhibition was related to a shift from the M1 microglial phenotype to the M2 microglial phenotype, thus reducing TBI-induced neuroinflammation. ADAM17 inhibition increased expression of TGF-βRs on the microglia membrane, promoted formation of TGF-β1/TGF-βRII complexes, and induced intranuclear translocation of Smads, which activated the TGF-β/Smad pathway. ADAM17 inhibition regulated microglia M1/M2 phenotype polarization through the TGF-β1/Smad pathway and influenced the neuroinflammatory response after TBI.ConclusionsMicroglial activation, the neuroinflammatory response, and the TGF-β1/Smad signaling pathway play essential roles in secondary injury after TBI. Specific inhibition of ADAM17 increased the expression of TGF-βRs on the microglia membrane and promoted formation of TGF-β1/TGF-βRII complexes. The TGF-β1/TGF-βRII complexes then induced intranuclear translocation of Smads, activated the TGF-β 1/Smad pathway, and regulated M1/M2 polarization of microglia, which influence the neuroinflammatory response as well as play a neuroprotective role after TBI

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ADAM17-deficiency on microglia but not on macrophages promotes phagocytosis and functional recovery after spinal cord injury

Cited by 27 publications

References 60 publications

The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

ADAM17 Aggravates the Inflammatory Response by Modulating Microglia Polarization Through the TGF-β1/Smad Pathway Following Experimental Traumatic Brain Injury

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ADAM17-deficiency on microglia but not on macrophages promotes phagocytosis and functional recovery after spinal cord injury

Cited by 27 publications

References 60 publications

The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

ADAM17&nbsp;Aggravates the Inflammatory Response by Modulating Microglia Polarization Through the TGF-β1/Smad Pathway Following Experimental Traumatic Brain Injury

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ADAM17 Aggravates the Inflammatory Response by Modulating Microglia Polarization Through the TGF-β1/Smad Pathway Following Experimental Traumatic Brain Injury