Upregulation of non-canonical and canonical inflammasome genes associates with pathological features in Krabbe disease and related disorders

Abstract

Infantile Krabbe disease is a rapidly progressive and fatal disorder of myelin, caused by inherited deficiency of the lysosomal enzyme β-galactocerebrosidase. Affected children lose their motor skills and other faculties; uncontrolled seizures are a frequent terminal event. Overexpression of the sphingolipid metabolite psychosine is a pathogenic factor, but does not fully account for the pleiotropic manifestations and there is a clear need to investigate additional pathological mechanisms. We examined innate immunity, caspase-11 and associated inflammatory pathways in twitcher mice, an authentic model of Krabbe disease. Combined use of molecular tools, RNAscope in situ hybridization and immunohistochemical staining established that the expression of pro-inflammatory non-canonical caspase-11, canonical caspase-1, gasdermin D and cognate genes is induced in nervous tissue. Early onset and progressive upregulation of these genes accompanies demyelination and gliosis and while the molecules are scant in healthy tissue, abundance of the respective translation products is greatly increased in diseased animals. Caspase-11 is found in reactive microglia/macrophages as well as astrocytes but caspase-1 and gasdermin D are restricted to reactive microglia/macrophages. The inflammasome signature is not unique to Krabbe disease; to varying degrees, this signature is also prominent in other lysosomal diseases, Sandhoff and Niemann-Pick Type-C1, and the lysolecithin toxin model of focal demyelination. Given the potent inflammatory response here identified in Krabbe disease and the other neurodegenerative disorders studied, a broad induction of inflammasomes is likely to be a dominant factor in the pathogenesis, and thus represents a platform for therapeutic exploration.

Globoid Cell Leukodystrophy (Krabbe Disease): An Update

“…Caspase-11 was also found in reactive microglia/macrophages as well as in astrocytes, but caspase-1 and gasdermin D were restricted to reactive microglia/macrophages. 68 These results suggest that innate immune system might be involved in the inflammatory reactions associated with KB and twitcher mice. The role of the Pyroptosis process which utilizes gasdermin D and inflammasomes, in linking innate and adaptive immunity has been described.…”

From pathological mechanisms in Krabbe disease to cutting‐edge therapy: A comprehensive review

“…On the other hand, the accumulation of GalSph induces lipid raft disturbance (13) and AKT pathway alteration (14) and EV release (15), resulting in impairment of synaptic plasticity and myelination and in neurodegeneration (16) 9,50,52,63,66 . Furthermore, myelin debris, resulting from various mechanisms such as lipid raft alteration and dysfunction of oligodendrocytes and Schwann cells, are phagocytosed by microglia, inducing microglial activation (17) and astrogliosis (18) 67 . This activation leads to the release of cytokine (IL‐1 α and IL‐1 β) (19) with increasing neuroinflammation (10) and oligodendrocytes and Schwann cell alteration (20) 67 .…”

“…Furthermore, myelin debris, resulting from various mechanisms such as lipid raft alteration and dysfunction of oligodendrocytes and Schwann cells, are phagocytosed by microglia, inducing microglial activation (17) and astrogliosis (18) 67 . This activation leads to the release of cytokine (IL‐1 α and IL‐1 β) (19) with increasing neuroinflammation (10) and oligodendrocytes and Schwann cell alteration (20) 67 . Moreover, macrophages are transformed into globoid cells (characteristic multinucleated of KD) (21) 28 .…”