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. This article is part of the Special Issue "Lysosomal Storage Disorders".

Keywords: heparan sulphate; inflammasome; inflammation; innate immunity; lysosomal dysfunction; mucopolysaccharidosis.

Figure 1

Toll‐like receptor 4 (TLR4) signalling in response to a danger signal. PAMPs and danger‐associated molecular patterns (DAMPs) bind TLR4 resulting in MyD88 adaptor protein recruitment. This leads to the assembly of an IRAK4/IRAK1/IRAK2/TRAF6 complex. The IRAK1/TRAF6 complex binds a secondary complex, TAB2/TAK1/TAB1. This allows TRAF6 to dislocate from IRAK1 and move into the cytoplasm of the cell, whereby it can lead to the activation of various transcription factors, and initiation of a pro‐inflammatory response. Endocytosed‐TLR4 bound to its respective ligand is able to signal via TRIF in order to transcribe interferon transcription factors.

Figure 2

Proposed role of MPSIIIA heparan sulphate (HS) in innate immunity. HS is synthesised in the endoplasmic reticulum‐Golgi, where it undergoes chain modification events. It is likely that MPSIIIA HS is highly sulphated due to an increase in activity of the chain modification enzyme NDST. HS bound to a proteoglycan (HSPG) is exocytosed to the cell membrane. In its HSPG form it may interact with the TLR4‐MD2‐CD14 complex to propagate an inflammatory response. HS may also be cleaved by heparinase, an endoglycosidase which has been seen to be up‐regulated in cancer metastasis and neuroinflammation. Increased heparanase activity would digest HS to short fragments which may have the potential to bind the TLR4‐MD2‐CD14 complex. In order to degrade HS, HSPGs are endocytosed and digested within the endolysosome, the deficiency in SGSH which is the primary cause of MPSIIIA, would result in HS fragments which are highly sulphated with a sulphated non‐reducing end residue. These fragments may either undergo exocytosis and subsequent binding to the TLR4 complex, or be released intracellularly due to lysosomal destabilisation and directly activate the NLRP3 inflammasome.

Figure 3

Pathways regulating NLRP3 inflammasome activation. Various stimuli, such as excessive ATP, viral RNA and particulate matter (e.g. protein aggregates or crystalloid structures) have the ability to activate the NLRP3 inflammasome and induce the maturation and secretion of interleukin‐1β (IL‐1β). An excess of ATP, and most other NLRP3 activators bring about the efflux of K⁺. An increase in intracellular Ca²⁺ from intracellular stores or via transmembrane transporters has been associated with NLRP3 inflammasome activation. The production of reactive oxygen species (mtROS), as a result of mitochondrial dysfunction is another potential driver of inflammasome activation. Lastly, particulate matter taken up via phagocytosis can lead to lysosomal membrane permeabilisation, the leakage of cathepsin B and other cysteine proteases and NLRP3 inflammasome activation.