The role of innate immunity in mucopolysaccharide diseases

Abstract

Mucopolysaccharidoses are lysosomal storage disorders characterised by accumulation of abnormal pathological glycosaminoglycans, cellular dysfunction and widespread inflammation, resulting in progressive cognitive and motor decline. Lysosomes are important mediators of immune cell function, and therefore accumulation of glycosaminoglycans (GAGs) and other abnormal substrates could affect immune function and directly impact on disease pathogenesis. This review summarises current knowledge with regard to inflammation in mucopolysaccharidosis, with an emphasis on the brain and outlines a potential role for GAGs in induction of inflammation. We propose a model by which the accumulation of GAGs and other factors may impact on innate immune signalling with particular focus on the Toll‐like receptor 4 pathway. Innate immunity appears to have a dominating role in mucopolysaccharidosis; however, furthering understanding of innate immune signalling would have significant impact on highlighting novel anti‐inflammatory therapeutics for use in mucopolysaccharide diseases. https://onlinelibrary.wiley.com/page/journal/14714159/homepage/virtual_issues.htm.

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…The protease CTSS is preferentially expressed in cells of the macrophage/monocyte lineage, and inflammation stimulates its secretion from the microglia and macrophages [185,187]. The involvement of microglial CTSB, CTSD, and CTSS in neurodegenerative diseases supports the view that microglia-driven neuroinflammation contributes to the progression of neurodegeneration in MPS I and IIIB [183,188,189]. Indeed, molecular evidence of microgliosis has been well established in mouse and dog models of MPS I and MPS III A, B, and C subtypes [166,182,188,190].…”

“…Interestingly, enhanced expression and activity of CTSB resulted in being associated with increased deposition of amyloid plaques in the MPS I mouse brain, and the existence of a novel CTSB-associated amyloidogenic pathway leading to neurodegeneration was highlighted [165]. Since CTSB is a crucial regulator of the NLRP3 inflammasome, it likely contributes to the inflammasome-dependent pathway involved in MPS neuroinflammation [183]. On the other hand, the cysteine CTSB and the aspartate CTSD result to be up-regulated in a variety of neurological disorders [184][185][186].…”

“…However, in MPSs, the pathogenesis of the skeletal and joint disease, including growth impairment, may involve complex molecular mechanisms underlying alterations of cartilage and bone metabolism, as well as inflammatory pathways [197]. Indeed, metabolic inflammation is a significant cause of osteoarticular symptoms in MPS disorders [183,198]. On the other hand, CTSs have long been involved in skeletal and bone health and disease [199].…”

Lysosomal storage disorders: pathology within the lysosome and beyond

“…; Cho et al . ; Parker and Bigger ) as well as comprehensive overviews of lysosomal biology (Bajaj et al . ), CNS metabolism (McKenna et al .…”

“…Continuing on the theme of neuroinflammation is a comprehensive review by Parker and Bigger summarizing evidence for innate immune involvement in the group of mucopolysaccharidoses (MPS) and the potential role of Toll‐like receptor 4‐mediated signaling elicited by pathological storage material that accumulates in this group of LSDs (Parker and Bigger ). MPS diseases are caused by mutations in lysosomal enzymes responsible for the degradation of glycosaminoglycans (GAGs), culminating in the accumulation of partially degraded GAG sugars.…”