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Fig. 2 | Molecular Neurodegeneration

Fig. 2

From: The role of inflammation in neurodegeneration: novel insights into the role of the immune system in C9orf72 HRE-mediated ALS/FTD

Fig. 2

Major inflammatory pathways. A The JAK-STAT pathway regulates the cellular response to cytokines and growth factors and signals through dimerization of receptors upon binding of these molecules. Upon dimerization, a series of autophosphorylation and transphosphorylation events of the receptors and their associated JAK proteins results in an active STAT dimer that functions as transcription activator. B The MAPK and NF-κB pathway is characterized by a multi-step signaling cascade upon receptor activation eventually resulting in MAPK activation. In this cascade, generally a MAPK kinase kinase (MAP3K) phosphorylates and activates a MAPK kinase (MAP2K) which in turn activates the MAPK. Meanwhile, the MAP3K can also induce NF-κB signaling. Together with the transcription factor activator protein 1 (AP-1) activated by phosphorylation of the MAPK, NF-κB translocates to the nucleus and functions as a transcription factor. C The NLRP3 inflammasome pathway can be initiated by a plethora of different mechanisms that result in activation of the NF-κB pathway. The presence of additional cellular insults will result in the formation of the NLRP3 inflammasome which is able to activate caspase 1. The activated caspase 1 dimer is subsequently able to process gasdermin D, pro-IL-1β and pro-IL-18 into their mature forms causing the formation of a gasdermin D pore resulting in pyroptosis and the release of inflammatory cytokines. AP-1: activator protein 1; ATP: adenosine triphosphate; ASC: apoptosis associated speck-like protein containing a CARD; DAMP: damage-associated molecular pattern; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α; IKKα/β: Inhibitor of nuclear factor kappa-B kinase subunit alpha α/β; IL: interleukin; IL1-R: interleukin-1 receptor; IRAK1/4: interleukin-1 receptor-associated kinase 1/4; JAK: janus kinase; JNK: c-Jun N-terminal kinase; MAP2Ks: mitogen-activated protein kinase kinases; mtDNA: mitochondrial DNA; mtROS: mitochondrial reactive oxygen species; MyD88: myeloid differentiation primary response 88; NEK7: NIMA-related kinase 7; NEMO: NF-κB essential modulator; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NLR family pyrin domain containing 3; P2X4/7: ATP-gated P2X receptor cation channel 4/7; p38: p38 mitogen-activated protein kinase; PAMP: pathogen-associated molecular pattern; STAT: signal transducer and activator of transcription; TAB1,2,3: TGF-β activated kinase 1 binding protein 1, 2 or 3; TAK1: TGF-β activated kinase 1; TLR: toll-like receptor; TRAF6: TNF receptor associated factor 6

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