The Roles of Lysosomes in Inflammation and Autoimmune Diseases

Abstract

Lysosomes perform a range of functions, some of which, such as degradation, are common to all cell types. Others, such as secretion or lysosomal exocytosis, are more specialised and tend to involve fusion of this organelle with the cell surface to release its contents. This review describes lysosomal regulation of the inflammatory glucocorticoid signaling pathways, and summarizes the roles of lysosomes in negatively or positively modulating the production of inflammatory cytokines. We also review the characteristic changes in lysosomal hydrolases and membrane proteins in common autoimmune diseases. Finally, future directions in lysosome research are proposed, with it being suggested that the role of lysosomes will continue to be of growing interest in immunity research.

Full text

International Reviews of Immunology, Early Online:1–17, 2014
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ISSN: 0883-0185 print / 1563-5244 online
DOI: 10.3109/08830185.2014.936587
REVIEW ARTICLE
The Roles of Lysosomes in Inflammation
and Autoimmune Diseases
Wei Ge,1,∗Dongxu Li,2,∗Yanpan Gao,1and Xuetao Cao1
1National Key Laboratory of Medical Molecular Biology & Department of Immunology,
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Dongdan Santiao
5 #, Dongcheng district, Beijing, China; 2Key Laboratory of Structure-Based Drug Design &
Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang
Pharmaceutical University, Wenhua road 103 #, Shenhe district, Shenyang, China
Lysosomes perform a range of functions, some of which, such as degradation, are common to
all cell types. Others, such as secretion or lysosomal exocytosis, are more specialised and tend
to involve fusion of this organelle with the cell surface to release its contents. This review de-
scribes lysosomal regulation of the inflammatory glucocorticoid signaling pathways, and summa-
rizes the roles of lysosomes in negatively or positively modulating the production of inflamma-
tory cytokines. We also review the characteristic changes in lysosomal hydrolases and membrane
proteins in common autoimmune diseases. Finally, future directions in lysosome research are pro-
posed, with it being suggested that the role of lysosomes will continue to be of growing interest
in immunity research.
Keywords: autoimmune diseases, cytokines, inflammation, lysosome
INTRODUCTION
Lysosome is an organelle of eukaryotic cells that is critically involved in the degra-
dation of macromolecules mainly delivered by endocytosis and autophagocytosis.
Degradation is achieved by more than 60 hydrolases sequestered by a single phospho-
lipid bilayer. As early as 1979, it was reported that lysosomal enzymes can inactive the
glucocorticoid receptor-Hsp90 complex by ‘changing’ this complex to a smaller form,
preventing the interaction of GR and glucocorticoids. In 1997, Tanaka and Sakanaka
found that glucocorticoids promoted lysosomal vacuolation in microglial cells, and
that the GR mediated an increase in cytoplasmic vacuoles and a signicant suppres-
sion of acid phosphatase activity. In 2011, it was reported that lysosomes modulate
glucocorticoid signalling and the inammatory response. ese studies show that the
lysosomal activity is negatively correlated with the anti-inammatory eect of gluco-
corticoids, an eect which occurs through the glucocorticoids signalling pathway.
Accepted 13 June 2014.
∗ese authors contributed equally to this work.
Address correspondence to Dr. Wei Ge and Dr. Xuetao Cao, National Key Laboratory of Medical
Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese
Academy of Medical Sciences, Dongdan Santiao 5 #, Dongcheng district, Beijing 100005, China.
E-mail: wei.ge@chem.ox.ac.uk or caoxt@immunol.org

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In addition to glucocorticoid receptor regulation, secretory lysosomes can secrete
or degrade inammatory cytokines to regulate the release of cytokines (eg. IL-1β,IL-
18 and TNF-α) in the immune response. us, lysosomes can both positively and neg-
atively regulate inammation. A feedback mechanism exists to adjust the balance of
the inammatory response in cells and organelles. Furthermore, the involvement of a
lysosomal membrane protein (such as TMEM9B) in the activation of the NF-κBand
MAPK pathways suggests that the lysosomal compartments may play a central role in
the inammatory signalling network.
In this review, we discuss key recent ndings in the eld and highlight some of the
areas in which lysosomes play a role in inammation. We also reviewed the charac-
teristic changes in lysosomal hydrolases and membrane proteins in common autoim-
mune diseases. Finally, future directions in lysosome research are proposed, with it
being suggested that the role of lysosomes will continue to be of growing interest in
immunity research.
Lysosomes Degrade Glucocorticoid Receptors in Inflammatory Pathways
As early as 1979, it was reported that lysosomal enzymes can inactive the glucocorti-
coid receptor (GR)-Hsp90 complex by ‘changing’ this complex to a smaller form, pre-
venting the interaction of GR and glucocorticoids (GC) [1](BOX 1).
BOX 1
Anti-inflammation Mechanism of Glucocorticoids
Glucocorticoids (GCs), steroidal anti-inammatory drugs, are widely used for the
treatment of inammation. eir anti-inammatory eects are brought about by their
binding to the GR. e GR-GC complex is able to shuttle between the nucleus and
cytoplasm. In the inactive state, the GR forms a complex with Hsp90 and is localised
in the cytoplasm. When it is activated by binding GCs, the GR-GC dissociates from
the GR-Hsp90 complex with the conformational change in the GR, which enables GR-
GC to translocate into the nucleus [2]. As a transcription factor, the GR-GC complex
plays an anti-inammatory role via two major pathways: i) e GR-GC complex in-
teracts with nuclear factor κB(NF-κB) and activating protein 1 (AP-1), downregulat-
ing the expression of pro-inammatory genes, including IL-1β,IL-6andTNF-α; ii)
e GR-GC complex binds to glucocorticoid response elements (GRE) in the nucleus,
upregulating the expression of anti-inammatory genes, including lipocortin-1, β2-
adrenoceptor and annexin-1 [3, 4]. Both pathways ultimately act on the arachidonic
acid metabolic pathways, leading to reduced expression of PLA-2 and COX-2, thus de-
creasing prostaglandin (PG) secretion and suppressing inammation [5].
In 1997, Tanaka and Sakanaka found that GCs promoted lysosomal vacuolation in
microglial cells, and that the GR mediated an increase in cytoplasmic vacuoles and
a signicant suppression of acid phosphatase activity [6]. Since acid phosphatase ac-
tivity is characteristic of lysosomes, they proposed that lysosomes play a role in the
GR-mediated anti-inammation pathway. In 2011, He et al. demonstrated that lyso-
somes modulate GC signalling and the inammatory response [7]. ey found that
lysosomes promote inammation by fusing with autophagosomes and degrading the
GR (Figure 1). In He’s study, chloroquine, a weak base, was used to inhibit the activity
of lysosome by neutralising the acidic lysosomal enzymes. e combination of chloro-
quine and dexamethasone (Dex, a GC drug) signicantly relieved symptoms of arthri-
tis in a mouse model, indicating that combination therapy is more eective than Dex
alone. Other lysosomal function inhibitors, such as the V-ATPase inhibitor balomycin
A1, may also enhance the anti-inammatory activity of Dex. Moreover, a knockdown
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lysosome Inflammation Autoimmune Diseases 
Figure 1. GR-GC plays an anti-inammatory role via two pathways. First, by interacting with nu-
clear factor κB (NF-κB) and AP-1, GR-GC down-regulates the expression of pro-inammatory cy-
tokines, such as IL-1β, IL-6, and TNF-α. Second, by binding GRE of DNA in the nucleus, the
GR-GC dimer up-regulates the expression of anti-inammatory genes such as lipocortin-1, β2-
adrenoceptor and annexin1. Both pathways ultimately act on the arachidonic acid metabolic path-
ways, leading to the reduced expression of PLA-2 and COX-2, and decreased secretion of PGs, sup-
pressing inammation. But when GR is degraded through the lysosome-mediated autophagy path-
way, the abundance of GR in cytoplasm is reduced, and subsequent GR-GC anti-inammatory ac-
tivity is inhibited.
of transcription factor EB (TFEB), a lysosomal biogenesis regulator [8], decreased the
number of lysosomes in cells, subsequently increasing the concentration of GRs and
the anti-inammatory eect of Dex [7].
ese studies show that the lysosomal activity is negatively correlated with the anti-
inammatory eect of Dex, an eect which occurs through the GC signalling path-
way (Figure 1). is provides the theoretical basis for developing anti-inammatory
medicine combinations that consist of a lysosomal inhibitor and GCs, in order to re-
duce the dose of GCs, minimise GC side eects, improve ecacy and overcome GC-
drug resistance. ere is therefore a clear clinical rationale for the development of
lysosomal inhibitors. However, the dynamic regulating mechanismb etween lysosome
function and the GC signalling pathway remains unclear.
Lysosomes Regulate the Secretion of Inflammatory Cytokines
In addition to GR regulation, secretory lysosomes can secrete or degrade inamma-
tory cytokines to regulate the immune response (Table 1). Secretory lysosomes can un-
dergo regulated cytokine release in response to external stimuli, such as lipopolysac-
charide (LPS) and ATP (reviewed in [9]).
IL-1βand IL-18
Secretory lysosomes can either promote or suppress inammation, depending on the
stage of the inammatory response (Figure 2). Pro-inammatory eects occur primar-
ily as a result of the exocytosis of IL-1β[10];aninammatorysignal(suchasLPS)
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TABLE 1. Interactions between lysosome and cytokines.
Cytokines Interactions between lysosome and cytokines Reference
IL-1βPro-IL-1βis transformed into IL-1βby caspase-1 by
interacting with Rab39a in lysosomes. Active
IL-1βis secreted by lysosome exocytosis.
[10, 14]
IL-18 Similarly to IL-1β, IL-18 can reach the extracellular
space via secretory lysosomes. is process is
regulated by extracellular calcium inux along
the microtubular cytoskeleton.
[21, 22]
IL-6
IFN-β
TNF-α
Lysosome-associated small RabGTPase Rab7b
mediates inhibition of TLR4 and TLR 9 signaling,
which downregulate LPS-induced production of
TNF-α,IL-6andIFN-β.
[23, 30, 31, 33, 97]
IL-6 stimulation induces lysosome-dependent
degradation of gp130, which is critical for the
cessation of IL-6-mediated signaling.
Hypoxia enhances lysosomal TNF-αdegradation.
Secretion of TNF-αmay be localised to secretory
lysosomes; TNF-αcytotoxic signaling induces
lysosomalpermeabilisation.
IL-8 Lysosomal PGN processing is required for
production of TNF-αin monocytes and for IL-8
production in neutrophils. Lysosomal
hydrolase-modied LDL can trigger the
expression of IL-8 in macrophages.
[38, 39]
TGF-βSNX25 negatively regulates TGF-βsignaling by
enhancing the degradation of TGF-βreceptor I.
TGF-β1 increases its cellular expression of the
receptor (integrin α5β1) by preventing integrin
α5β1 degradation.
[36, 37]
promotes the synthesis and cytoplasmic accumulation of the IL-1βprecursor (pro-
IL-1β) which then translocates into secretory lysosomes together with caspase-1. is
translocation requires a pH dierence between the cytosol and the lysosomal lumen.
Caspase-1 is responsible for the transformation of the pro-IL-1βinto its mature form,
with the prerequisite that caspase-1 must interact with Rab39a (BOX 2) [11].
BOX 2
Interleukin-1β
Interleukin-1β(IL-1β), a potent pro-inammatory cytokine, is the most studied mem-
ber of the IL-1 family because of its role in mediating inammatory and autoimmune
diseases [12]. Most proteins that are secreted from the cell contain signal peptides that
direct their transport to the plasma membrane through the endoplasmic reticulum-
Golgi pathway. However, certain proteins, such as IL-1β, do not contain signal pep-
tides and are secreted by unconventional means. In the case of IL-1β, these include
secretory lysosomes, microvesicle shedding, membrane transporters and multivesic-
ular bodies (reviewed in [13]).
Rab39a
During an inammatory response, Rab39a is a tracking adaptor linking caspase-
1toIL-1βsecretion. Recombinant caspase-1 cleaves Rab39a at a highly-conserved
cleavage site. Pro-inammatory stimuli induce Rab39a expression, while Rab39a
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lysosome Inflammation Autoimmune Diseases 
Figure 2. e lysosome-mediated inammatory pathways. Pro-inammatory pathway:Exogenous
ATP activates cell membrane P2×7receptor resulting in K+eux. e consequent decrease in
the concentration of intracellular K+concentration promotes inammasome assembly and acti-
vates iPLA2, involved in transforming pro-caspase-1 into caspase-1. Caspase-1 is transported to
the lysosome lumen by an as-yet-unknown mechanism. In addition, decreased K+concentration
stimulates cytosolic phosphatidylcholine specic phospholipase C (PC-PLC), which activates Ca2+
pumps in the plasma membrane, resulting in the inux of Ca2+. e increasing intracellular con-
centration of Ca2+can activate cPLA2 that is suggested to promote the lysosome exocytosis pro-
cess. A fraction of cytoplasmic pro-IL-1βand pro-caspase-1 colocalise in secretory lysosomes and
are secreted together with lysosomal hydrolases such as cathepsin D. Anti-inammatory pathway:
some ightless (Flii) localises to lysosomes and is secreted through a lysosomal pathway. Fliican in-
hibit caspase-1 as a pseudosubstrate, suppressing caspase-1-mediated maturation of the cytokine
pro-IL-1βto IL-1βin macrophages, thus reducing IL-1βsecretion. In addition, secreted ightless
dampens the production of pro-inammation cytokines by binding to LPS.
knockdown reduced IL-1βsecretion (though pro-IL-1βmRNA levels are unchanged).
Rab39a regulates the activation of pro-IL-1βto give IL-1β, while the expression of
TNF-αis unchanged. erefore, Rab39a is specic for IL-1βsecretion. In contrast,
overexpression of Rab39a results in an increase in IL-1βsecretion, while overexpres-
sion of a Rab39a construct lacking the caspase-1 cleavage site leads to an additional
increase in IL-1βsecretion. erefore, cleavage of Rab39a by caspase-1 would appear
to serve as a mechanism for inactivating Rab39a, thereby reducing levels of IL-1βse-
cretion [11].
IL-1βand other lysosomal contents are released into the extracellular space af-
ter the fusion of lysosomes with the plasma membrane, which is driven by exoge-
nous ATP and by hypotonic conditions [10]. In 2004, Andrei and his colleagues ver-
ied the molecular mechanism of lysosome-mediated IL-1βsecretion [14] (Figure 2).
ey suggest that an increase in intracellular Ca2+during the secretion process mo-
bilises secretory lysosomes. is change occurs along microtubules close to the mi-
crotubule organizing center [15], and is proceeded by actin-based movement at the
cell periphery, towards the docking site at the plasma membrane. A number of lyso-
somal membrane proteins, e.g. soluble N-ethylmaleimide–sensitive factor attachment
protein receptors (SNARES) and the Rab-GTPase family, have a crucial role to play in
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intracellular protein movement [9–16] and fusion between secretory lysosomes and
the plasma membrane [17, 18] during the course of lysosome exocytosis. In short, ATP-
induced IL-1βprocessing occurs within the secretory lysosome, positively regulating
inammation.
Do lysosomes always have a positive regulatory function in inammation-
mediated processes? e ndings of Li et al. suggest not, as they have found that lyso-
somes can negatively modulate inammatory by secreting ightless [19]. Flightless, a
member of the gelsolin superfamily of actin-remodelling proteins, inhibits caspase-
1 by acting as a pseudo-substrate. is prevents caspase-1-mediated maturation of
the cytokine pro-IL-1βto IL-1βin macrophages,thus reducing IL-1βsecretion (Fig-
ure 2). e observation that knockdown of endogenous ightless enhances caspase-1
activity, and its overexpression inhibits caspase-1 activity and IL-1βmaturation [19]
supports this. In 2012, Lei et al. discovered that some ightless localised to lysosomes
and is secreted through a lysosomal pathway in broblasts and macrophages [20]. Se-
creted ightless inhibits the production of pro-inammatory cytokines by binding to
LPS (Figure 2). Moreover, LPS-stimulating macrophages or scratch-wounding brob-
lasts can upregulate the secretion of ightless, which in turn may have a modifying
eect on wound inammation and inhibit excessive cytokine production [20].
Similar to IL-1β, the secretion of IL-18 in dendritic cells (DCs) is also mediated by
secretory lysosomes and regulated by extracellular Ca2+inux [21].e reorganisa-
tion of cytoskeletal proteins is fundamental to this calcium-dependent process. e
role played by secretory lysosomes is evidenced by the observation that the release of
the lysosomal enzyme cathepsin D is comparable to the secretion of IL-18 in natural
killer/immature DC cocultures [22].
TNF-α
e pro-inammatory cytokine tumor necrosis factor alpha (TNF-α) can regulate both
cell survival and cell death, and can be regulated by lysosomes. e fate of TNF-αde-
pends on cellular oxygen levels [23]. It is not uncommon for inamed lesions to be-
come severely hypoxic due to the fact that hypoxia can generate inammation [24]. In
thecaseofnormoxiaTNF-αis conveyed from the early endosome to the secretory lyso-
somes via the lysosome, and nally to the plasma membrane. In the hypoxic inam-
matory micro-environment, TNF-αmoves from the membrane towards the lysosome,
enhancing its degradation [23]. Nitza et al. found that levels of TNF-αmRNA are un-
changed in hypoxia, but intracellular TNF-αprotein levels are decreased, and its secre-
tion in mouse peritoneal macrophages is suppressed. is suggests enhanced degra-
dation of TNF-αprotein in hypoxia [23]. Whilst the quantity of secreted TNF-αwas
unaected by the addition of the lysosome inhibitor balomycin A1, the degradation
of intracellular TNF-αwas dose-dependently inhibited. However, this only occurred
under hypoxia, from which it can be inferred that intracellular TNF-αis directed to the
lysosomes from the early endosomes, to boost its degradation during hypoxia [23]. To
the best of our knowledge, this is the rst time it has been reported that secretion of
TNF-αis localised to secretory lysosomes, though this intact pathway remains to be
established.
Bastow et al. found that the SNAREs superfamily members vesicle-associated mem-
brane protein (VAMP7 and VAMP8) potentially mediate lysosomal exocytosis in hy-
pertrophic chondrocytes [25]. is nding is intriguing in the context of osteoarthritis
(OA). While severe synovial inammation, such as that found in rheumatoid arthri-
tis, is absent in OA, moderate levels of joint inammation can be found. OA chon-
drocytes express inammatory cytokines including IL-1, TNF-αand IL-6. Pushparaj
et al. demonstrated that TNF-αcolocalises with VAMP8-containing vesicles, and that
in VAMP8-decient macrophages, TNF-αrelease is inhibited [26]. TNF-αrelease in
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lysosome Inflammation Autoimmune Diseases 
macrophages and proper tracking of secretory lysosomes for exocytosis both re-
quire the VAMP8 vesicle-associated-SNARE. Interestingly,the SNARE proteins VAMP7
and VAMP8 have previously been shown to mediate fusion of late endosomes and
lysosomes, respectively [27, 28]. It is tempting to speculate that as VAMP8 and TNF-
αare colocalised in secretory lysosomes, there may be a lysosome-associated path-
way mediating the secretion of TNF-α, as occurs for IL-1β. As explained above, in
inammation-induced hypoxia, lysosomes in the inammatory cells increase TNF-
αdegradation, thereby reducing its secretion and release. is reduces the pro-
inammatory eects of TNF-α. Furthermore, lysosomes are involved in inducing
apoptosis in the TNF-αcytotoxic signalling cascade; this pathway triggers lysosomal
permeabilisation, releasing the pro-apoptotic lysosomal protease cathepsin B into the
cytosol. us, TNF-αsets a complex signalling network into action. is network, in
which the lysosome has a key role, facilitates biological responses that range from
apoptosis to inammation. Further studies veried such conclusions at the molec-
ular level: in 2008, Francis et al. identied the lysosomal transmembrane protein 9B
(TMEM9B, an N-glycosylated protein) as an important component of the TNF sig-
nalling pathway and a module shared with the IL-1βand Toll-like receptor (TLR) path-
ways [29]. e fact that TMEM9B is crucial to the TNF-mediated activation of both the
NF-κB and MAPK pathways, but is not a prerequisite for TNF- or Fas ligand-induced
apoptosis, suggests that TMEM9B plays a specic role in inammatory cytokine sig-
naling [29]. e localisation of TMEM9B in lysosomes suggests that this organelle
is involved in the regulation of signal transduction downstream of inammatory
receptors.
IL-6, IFN-β,TGF-βand IL-8
IL-6, probably the most extensively studied cytokine, is generally regarded as a
pro-inammatory factor. Lysosomes are involved in the production of IL-6 and
its downstream signalling pathways. Wang et al. found that Rab7b (a lysosome-
associated small Rab GTPase) could serve as a negative regulator of TLR4 signalling
in macrophages by accelerating lysosomal degradation of TLR4 and decreasing the
plasma membrane TLR4 expression level [30]. is resulted in the hyposensitivity of
macrophages to LPS stimuli and inactivated the MAPK, NF-κB, and IRF3 pathways,
in turn down-regulating the LPS-induced production of TNF-α, IL-6 and IFN-β.Yao
et al. reported that Rab7b functions as a negative regulator of intracellular-localised
TLR9 signalling in macrophages by enhancing tracking of TLR9 to the lysosome
for degradation [31]. is led to the suppression of TLR9-triggered generation of pro-
inammatory cytokines such as TNF-α,IL-6,andIFN-βby impairing activation of
MAPK and NF-κB pathways. Rab7b-mediated inhibition of TLR4 and TLR9 signalling
may serve as a feedback mechanism to prevent excessive inammatory responses.
However, in some specic cells, Rab7 can also promote the production of IL-6. For
example, Rab7b plays an important role in megakaryopoiesis by activating NF-κBand
promoting IL-6 production [32].
e IL-6 receptor complex consists of two ligand-binding αsubunits and two
signal-transducing subunits known as gp130. Lysosomes can degrade gp130, reduc-
ing the net number of surface-bound gp130 molecules, thus reducing IL-6-dependent
STAT3 activation and downstream gene expression [33]. Tanaka et al. reported
that IL-6 stimulation induced lysosome-dependent degradation of gp130, which is
critical for cessation of IL-6-mediated signaling [34]. Furthermore, a complex inter-
action of diverse cytokines, that crosstalk on numerous levels, is part of the inamma-
tory response. Simone et al. found that IL-1βand TNF-αinduce gp130 internalisation
and its subsequent lysosomal degradation [35]. Consequently, the potential additive
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pro-inammatory eects of these cytokines are impeded by the inhibitory activity of
IL-1βand TNF-αon IL-6 signalling.
Lysosomes can block inammatory signalling pathways by degrading cytokines’ re-
ceptors, which are regulated by certain intracellular protein. For example, TGF-βsig-
nalling is negatively regulated by the protein sorting nexin (SNX25), a member of the
sorting nexin family, which performs cargo sorting and signalling functions within the
endocytic network. rough clathrin-dependent endocytosis and subsequent lyso-
some degradation, SNX25 enhances the degradation of the TGF-βreceptor I [36]. In-
ammatory cytokines can also inhibit the lysosomal degradation of their own recep-
tors. For example, TGF-β1 increases expression of its cellular receptor (integrin α5β1)
by preventing lysosome-mediated integrin α5β1 degradation [37]. Some inamma-
tory stimuli, such as Bacillus anthracis peptidoglycan (PGN), must be processed by the
lysosome in order to be identied by the corresponding receptors, as PGN itself is not a
stimulus for the sensor [38]. Lysosomal enzymes degrade PGN to a simpler moiety that
can be recognised by a cytoplasmic sensor, leading to subsequent production of TNF-
αin monocytes and IL-8 production in neutrophils [38]. Pro-inammatory agents can
also be regulated through extracellular secretion of lysosomal enzymes. For example,
cultured macrophages can release lysosomal acid lipases in the presence of inam-
matory stimuli. ese produce morphologically-modied Low-Density Lipoprotein,
known as hydrolase-modied Low-Density Lipoprotein [39], which was shown to ini-
tiate IL-8 expression in macrophages via activation of the p38 MAPK and NF-κBpath-
ways [39].
In summary, lysosomes can both positively and negatively regulate inammation.
We speculate that a feedback mechanism exists to adjust the balance of the inam-
matory response in cells and organelles. Following an inammatory stimulus, lyso-
somal secretion of pro-inammatory cytokines can promote inammation. However,
after prolonged or severe inammation, lysosomes can inhibit inammatory cytokine
production. A balance of both regulatory roles in the inammatory response en-
ables the body to maintain a state of equilibrium. Inammation is a protective re-
sponse of organisms to pathogens, irritation or injury. Whereas restricted inamma-
tion is benecial, excessive or persistent inammation incites tissue destruction and
disease. A disturbed balance between the activation and inhibition of inammatory
pathways can set the stage for chronic inammation, which is increasingly recog-
nised as a key pathogenic component of autoimmune, metabolic, cardiovascular and
neurodegenerative disorders [40]. erefore, the positive and negative regulation of
inammation by “exible” lysosomes plays a signicant role in maintaining the pro-
/anti-inammatory balance. Furthermore, the involvement of a lysosomal membrane
protein (such as TMEM9B) in the activation of the NF-κBandMAPKpathwayssug-
gests that the lysosomal compartments may play a central role in the inammatory
signalling network. It is possible that lysosomes contain more membrane proteins as-
sociated with inammation, which are involved in the regulation of intracellular sig-
nalling pathways. ese proteins are potentially new drug targets for the development
of anti-inammatory combination treatments.
Lysosome and Autoimmune Diseases
e lysosomal compartment plays a central role in a variety of cellular pathways that
are important for normal immune system function. For example, a functional lysoso-
mal compartment is required to process and present antigens, allowing MHC-I and
MHC-II to exert their immunomodulatory eects [41].
In autoimmune diseases, organisms produce autoantigens (such as nuclear anti-
gens) that the immune system cannot distinguish from normal antigens. Lysoso-
mal enzyme activity controls the generation of autoantigens. For example, lysosomal
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lysosome Inflammation Autoimmune Diseases 
a-galactosidase A (a-Gal-A) degrades lipid antigens to prevent their accumulation and
activation of the self lipid-reactive and CD1d-restricted NKT cells. Deciency in a-
Gal-A causes aberrant accumulation of lipid antigens and activation of immature NKT
cells, resulting in autoimmunity [42]. In the MHC-II-mediated autoantigen processing
and presentation pathway, the lysosome is like a key signalling hub, where endocytic,
exocytic and degradation pathways intersect (BOX 3) (Table 2).
BOX 3
MHC-II-mediated Autoantigen Presentation Pathway
Within the lysosomes of antigen presenting cells (APCs, e.g. DCs), self-antigens are
degraded into antigenic peptides by lysosomal proteases. After synthesis in the en-
doplasmic reticulum, MHC-II is associated with the invariant chain (Ii). On stimu-
lation, it is targeted to lysosomes (here also called MHC-II compartments), where
lysosomal cathepsin S degrade Ii, leading to MHC-II maturation (for details see [43,
44]). Newly-synthesised MHC-II binds antigenic peptides to form the MHC II-peptide
complex on the lysosome membrane. MHC-II-containing lysosome exocytosis and fu-
sion with the plasma membrane ultimately delivers the peptide-MHC II complexes to
the cell surface [45]. Activated DCs express co-stimulatory molecules of MHC II (e.g.
CD28, CD40L) and eciently present autoantigen peptides to CD4+helper T-cells.
ese then activate B cells to become plasma cells, which subsequently produce large
amounts of autoantibodies [46].
Due to the loss of self-tolerance, the immune system processes and presents these
autoantigens as usual, subsequently inducing the production of autoantibodies. e
autoantibodies react with self-components which are often macromolecular com-
plexes of proteins and nucleic acids, in the nucleus and cytoplasm to form immune
complexes that can accumulate in the kidneys and other tissues and lead to autoim-
mune diseases [47]. e next section summarises the critical role of lysosomes in some
common autoimmune diseases, including systemic lupus erythematosus (SLE) and
rheumatoid arthritis (RA).
Lysosomes and SLE
SLE is a multi-factorial disease characterised by autoimmune responses against self-
antigens generated by dying cells. A deciency in the clearance of apoptotic cells
is thought to be one of the causes of SLE [48]. Apoptotic cells are engulfed by
macrophages, and then transferred to lysosomes. Here, their components are de-
graded into amino acids, nucleotides, fatty acids and monosaccharides by lysoso-
mal enzymes. For example, DNase II-like acid DNase and cathepsins degrade the nu-
cleosomes of apoptotic cells [49]. If the degradation does not occur properly, dead
cell components (especially the nucleosomal DNA) accumulate in the lysosomes,
leading to the intracellular activation of the innate immune system to produce pro-
inammatory cytokines, such as IFN-βand TNF-α[50]. e increased levels of the
pro-inammatory cytokines are believed to play a role in the pathogenesis of SLE [51],
so cytokines have been suggested as therapeutic targets in SLE (reviewed in [52]).
Obvious changes take place in the lysosome membrane proteins and lysosomal
enzymes in the pathogenesis of SLE, which provide some evidence for the role of
lysosomes in the SLE pathogenesis. It has been proposed that a possible gauge
for disease activity in patients with SLE, could be the manifestation of lysosome-
associated membrane proteins (LAMPs) on the surface of peripheral blood mononu-
clear cells (PBMCs) [53]. Shayman et al. discovered, cloned and characterised lysoso-
mal phospholipase A2 (LPLA2) [54, 55]. ey found that LPLA2 knockout mice, older
than one year, have abnormal serologies, including anti-dsDNA antibodies, positive
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TABLE 2. Lysosomes and autoimmune diseases.
Autoimmune
diseases
Negative role or characteristic change of lysosomal enzymes in these
diseases
Diagnostic indicators and therapeutic
targets Reference
Systemic lupus
erythematosus
(SLE)
Lysosomal degradation breakdown of dead cells leads to production of
pro-inammatory cytokines, such as IFN-βand TNF-α.
Lysosome-localised TLRs mediate the production of IFN-αwhichhas a
crucial role in the pathogenesis of SLE.
Expression of Lamps on PBMC surface.
LPLA2 activity.
[50, 53, 57]
Rheumatic
arthritis (RA)
Cathepsin K is a critical protease in synovial broblast-mediated collagen
degradation and is elevated in the serum of RA patients [50–53].
Cathepsin S is signicantly upregulated in the synovial uids from RA
patients [59,60]. Cathepsin L has a signicant impact on RA severity
[63]. Lysosomal exoglycosidases participate in the destruction of the
articular cartilage [65].
Activity levels of lysosomal exoglycosidases
and cathepsins K, S and L.
[60, 61, 63, 69, 70, 73, 75]
Psoriasis In psoratic epidermis, cathepsins L, B and D are partially processed to
activated mature forms, where they are presented high percentage and
difuse expression in psoriatic epidermis. e degradative capacity of
cathepsin D is responsible for the disordered dierentiation and scale
formation characteristic of psoriasis.
DC-LAMP levels are higher in psoriasis
vulgaris lesions.
[82–86]
Multiple
sclerosis(MS)
Cathepsin S upregulation in MS patients during the relapse state, in RNA
form from peripheral blood leucocytes and in serum proteins.
Cathepsins S and D exist from precursor to mature forms in the CD34+
hematopoietic stem cells (HSCs) and are markedly more abundant in
the acute-MS group as compared to the stable-MS.
e levels of Cathepsins S and D expression
in the CD34+HSCs.
[87, 88]
Sj¨
ogren’s
syndrome (SjS)
Increased activities of lysosomal glycosidases and peptidases were found
in leukocytes from subjects who had been suering from SjS for more
than 5 years. Cathepsin S and H activities are signicantly higher in the
SjS mouse model than in control lysates.
Lysosomal β-glucuronidase and dipeptidyl
peptidase I as SjS marker enzymes.
Cathepsin S expression in tears
represents a biomarker for diagnosis of
SjS.
[89, 90]
Graves’ disease Graves’ hyperthyroidism is accompanied by a general increase in the
activity of the serum lysosomal glycolsidases.
e serum lysosomal glycolsidases activity. [91]
Type 1 diabetes
(T1D)
e Cathepsin L mRNA expression of peripheral CD8+T cells from T1D
model mice is signicantly increased compared with that of control
mice. Cathepsin S or cathepsin B deciency in NOD mice leads to a
decrease in T1D incidence, whereas deciency in cathepsin L exhibit
complete resistance to the disease. Cathepsin G activity is higher in
PBMCs from T1D patients compared to controls. Cathepsin G is
involved in proinsulin (autoantigen of T1D) processing.
Inhibition of cathepsin L as a powerful
therapeutic strategy for autoimmune
diabetes. Cathepsin G inhibitor reduces
proinsulin-reactive T cell activation.
[94–96]

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lysosome Inflammation Autoimmune Diseases 
anti-nuclear antibodies, and high circulating immunoglobulin levels. ey also de-
velop lymphoid hypertrophy and glomerulonephritis. is autoimmune phenotype
resembles SLE [56]. us, LPLA2 activity has been suggested as a diagnostic and ther-
apeutic target for SLE patients [57].
IFN-αhas a crucial role in the pathogenesis of SLE including direct and indirect
eects on APCs, T cells and B cells (reviewed in [58]). e lysosome-localised TLR-
mediated innate immune pathways regulate the production of IFN-α, TLR7 and TLR9.
ey occur in an inactive state in the plasmacytoid DCs of the Golgi complex, and are
cleaved and activated in the lysosomes by acidic proteases. ey can thusly interact
with nucleic acids (single-strand RNA in the case of TLR7, DNA in the case of TLR9)
that specialised receptors, such as Fcγreceptors, present to lysosomal compartments
[59]. Activated TLRs stimulate the production of IFN-αvia the MyD88-dependent
IRF5/IRF7 pathways. is IFN-α-inducing activity can be inhibited by lysosome in-
hibitors such as chloroquine or balomycin A, blocking the activation of TLR7 and
TLR9 [47].
In summary, lysosomes are implicated in the promotion of MHC class II presenta-
tion of autoantigens, degradation of apoptotic cells and the production of cytokines in
patients with SLE.
Lysosomes and RA
RA is an autoimmune disease with unknown etiology, but it is probably a result of loss
of self-tolerance. One of the disease hallmarks of RA is progressive cartilage and bone
destruction in the joints, which is caused by the increased activity of a huge number
of proteases that are secreted by several cell types in arthritic joints, such as synovial
broblasts and osteoclasts.
Lysosomal cysteine cathepsins have been identied as proteases that could poten-
tially be involved in the pathogenesis of RA. For example, cathepsin K is a critical
protease in synovial broblast-mediated collagen degradation [60, 61]. Skoumal et al.
demonstrated that cathepsin K is elevated in the serum of patients with RA [62]. Over-
expression of cathepsin K in transgenic mice makes them susceptible to progressive
synovitis, which results in degradation of articular cartilage and bone [63]. However,
the results of Schurigt et al. also point to alternative cathepsin K–independent mecha-
nisms for bone destruction. ey studied the eect of cathepsin K knockout in human
TNF-transgenic mice (hTNFtg mice). ese mice are used as a model of human RA,
and have chronic polyarthritis, similar to human RA, with spontaneously developing
inammation and bone destruction. Cathepsin K knockout partially inhibited, but did
not prevent, arthritic bone resorption [64, 65]. Nonetheless, cathepsin K is a valuable
parameter for the assessment of bone metabolism in patients with established RA.
Pharmacological inhibitors of cathepsin K such as MK-0822 [66], L-006235 [67] and
icariin [68], have been studied extensively for the purpose of preventing bone erosion
andjointdestructioninRA.
Cathepsin S is integral to the processing of MHC class II–Ii in autoantigen-
presenting cells, which produces class II molecules that are competent for bind-
ing antigenic peptides. Cathepsin S knockout mice had a decreased susceptibility to
RA and presented reduced invariant chain processing in B cells and DCs alike [69].
Cathepsin S is signicantly upregulated in the synovial uids from RA patients, consis-
tent with its crucial role in the MHC class II-mediated immune response [70]. Cathep-
sin S inhibitors show potential for use in the treatment of autoimmune diseases. For
instance, Weidauer et al. described the ecient inhibition of cathepsins K and S by
two gold derivatives (auranon and gold thiomalate) [71]. CSI-75, a potent and se-
lective cathepsin S inhibitor, suppressed clinical signs and symptoms in experimental
models of RA [72].
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 W. Ge et al.
e severity of antigen-induced arthritis (AIA, a  cell-dependent RA model) is in-
hibited in cathepsin L knockout mice, as characterised by reduced swelling, decreased
inammation and bone destruction [73]. In this study, the researchers proposed that
cathepsin L has a signicant impact on RA severity by inuencing the selection of 
cell population in the thymus, but it seems not to play any signicant role in direct joint
destruction. In 2004, Schedel et al. showed that ribozymes cleaving cathepsin L mRNA
are able to both decrease the synthesis of cathepsin L and reduce the invasion of RA-
SF (synovial broblasts) into cartilage and subsequent cartilage destruction [74]. By
cleaving glycoside bonds in glycoproteins and proteoglycans, lysosomal exoglycosi-
dases (including β-glucuronidase, β-galactosidase, hexosaminidase, α-mannosidase
and α-fucosidase) contribute to the destruction of the articular cartilage [75]. e
serum of patients with RA shows a notable increase in the activity of all exoglycosi-
dases, and likewise almost all exoglycosidases (with the exception of β-galactosidase
and α-mannosidase) show increased activity in synovial uid, with hexosaminidase
as the principal enzyme [75].
TNF-αis a major cytokine in the pathogenesis of RA, orchestrating synovial inam-
mation and bone degradation. For example,RA synovial broblasts are stimulated by
TNF-αto multiply and generate chemokines, growth factors, proteinases and adhe-
sion molecules and it is thusly vital to the RA disease process [76]. Autophagy is a
lysosome-mediated catabolic process that is also involved in autoimmune diseases.
Continuous removal of these proteins by the lysosome-autophagy and ubiquitin-
proteasome protein degradation pathways is necessary for survival of synovial brob-
lasts. Both pathways are more active in RA synovial broblasts than inother broblasts
[77]. In addition, Lin et al. veried the role of autophagy in joint destruction in RA [78].
ey demonstrated that autophagy is activated by TNF-αin RA osteoclasts, and stim-
ulates osteoclast dierentiation and bone destruction.
In contrast to their aforementioned role in promoting tissue damage in RA, lyso-
somes may also exert a protective role: human six-transmembrane epithelial antigen
of prostate 4 (STEAP4), localised in lysosomes, is regulated by TNF-αin synovium,
where it inhibits IL-6/IL-8 secretion and proliferation of broblast-like synoviocytes.
ese ndings suggest that STEAP4 might potentially suppress the pathogenesis of
TNF-α-induced RA [79].
During arthritis, the lysosomal membrane is altered, causing lysosomes to fuse
with the cell membrane and extrude the aforementioned enzymes. Accordingly,
recent drug development eorts have focused on enhancing lysosomal stability to pre-
vent the release of these enzymes in order to reduce the pain suered by RA patients
[80, 81]. In summary, during the RA pathological process, a variety of active enzymes
from the lysosome are secreted into the jointcavity, damaging articular cartilage. In
contrast, some lysosomal proteins such as STEAP4 can suppress RA by inhibiting in-
ammatory cytokine production or the proliferation of broblast-like synoviocytes.
Lysosomal Proteases in Some Common Autoimmune Diseases
Lysosomal proteases (also known as cathepsins) have been shown to play a signicant
role in some common autoimmune diseases.
Psoriasis is a chronic autoimmune skin disease characterised by epidermal hy-
perproliferation and inltration of inammatory leukocytes. In normal epidermis,
cathepsins L, B and D exist in an inactive, precursor form. However, in psoriatic epi-
dermis, these cathepsins are partially processed to activated enzymes. In view of their
high percentage and diuse expression in psoriatic epidermis, they may play a role in
the pathogenesis of psoriasis [82]. e degradative capacity of cathepsin D is respon-
sible for the disordered dierentiation and scale formation characteristic of psoria-
sis [83]. Cathepsin S expression is upregulated in psoriatic keratinocytes, but not in
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lysosome Inflammation Autoimmune Diseases 
actinic keratosis. Keratinocytic cathepsin S expression is activated by the cytokines
IFN-γand TNF-a, T-cells and atopic dermatitis keratinocytes. Cathepsin S is involved
in MHC class II expression and invariant chain (Ii) degradation in keratinocytes [84].
Compared with normal tissues, the levels of DC lysosome-associated membrane
protein (DC-LAMP) are higher in psoriasis vulgaris lesions, which suggest lysosomes
may be associated with the altered dierentiation of keratynocytes in psoriasis [85,
86]. On the other hand, DC-LAMP is involved in the synthesis and intracellular trans-
portation of the MHC-antigen complex of DCs and serves as a reliable DC maturation
marker [85].
Multiple sclerosis (MS) is a central nervous system autoimmune disease charac-
terised by inammation, demyelination and neurodegeneration. Elevated cathepsin
S levels have been observed in MS patients during the relapse state, in comparison
with healthy individuals [87]. mRNA levels of cathepsin S were increased in periph-
eral blood leucocytes and protein levels were increased in serum, consistent with pre-
vious observations of raised cathepsin S levels in other autoimmune diseases [87]. Re-
cently, a study revealed a correlation between cathepsin S and D expression and MS
clinical stage [88]: both lysosomal proteases are in an undeveloped form in the CD34-
positive hematopoietic stem cells (HSCs) isolated from the peripheral blood of healthy
persons, whereas the same cells from acute-MS patients consistently display mature
enzymes. In addition, mature forms of both enzymes are markedly more abundant
in HSCs from the acute-MS patients when compared to their stable-MS counterparts.
erefore, doctors can qualitatively assess cathepsin S and D expression in CD34+
HSCs for MS diagnostic purposes.
Sj¨
ogren’s syndrome (SjS) is a chronic autoimmune disease characterised by lym-
phocytic inltration and destruction of lacrimal glands and salivary glands. In
the rst 5 years after diagnosis, activity of the lysosomal peptidases (cathepsin B,
cathepsin D, dipeptidyl peptidase I, and tripeptidyl peptidase I) and also of the
lysosomal glycosidases(β-galactosidase, α-mannosidase, β-glucuronidase and β-
hexosaminidase) was elevated in the leukocytes of patients with SjS. is activity fur-
ther intensied between 5 and 10 years after diagnosis [89]. us, lysosomal enzyme
activities in the leukocytes of subjects with SjS appeared to shadow the state of the dis-
ease in the rst 10 years. e changes in lysosomal enzyme activities indicate that these
enzymes may play a role in SjS-associated tissue injury by accelerating the breakdown
of glycoproteins in lysosomes [89]. Studies in an SjS mouse model revealed elevated
cathepsin S and H activities in lysates, and increased cathepsin S levels in tears. is
correlates with the initiation of SjS and may therefore provide a biomarker for the di-
agnosis of autoimmune dacryoadenitis in humans [90].
Graves’ disease is an autoimmune disorder typically characterised by hyperthy-
roidism. Graves’ hyperthyroidism is accompanied by a general increase in lysosomal
glycolsidase activity in serum [91]. About 25 to 50% of patients with Graves’disease suf-
fer from Graves’ ophthalmopathy, a complex eye and orbital disorder that is uniquely
linked to Graves’ hyperthyroidism. Lysosome-related genes, such as CLN2, CLN3, and
HEXB, may be involved in the pathogenesis of adipose tissue hypertrophy in Graves’
ophthalmopathy [92].
Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell-mediated
destruction of pancreas islet βcells. e gene encoding the lysosomal membrane pro-
tein GIMAP5 is mutated in the BB rat model, resulting in a tendency to develop au-
toimmune T1D [93]. In peripheral CD8+T cells from non-obese diabetic (NOD) mice
which develop spontaneous T1D, cathepsin L mRNA levels are signicantly increased
compared with those of control mice [94]. e cytotoxic activity of CD8+T cells against
the islets in NOD mice with T1D may possibly be regulated by Cathepsin L [94]. In-
hibition of cathepsin L has been demonstrated to be a new therapeutic strategy for
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 W. Ge et al.
autoimmune diabetes in vivo by the administration of siRNA targeting the cathepsin
L gene [94]. In addition, a deciency in cathepsin S or cathepsin B in NOD mice re-
duced the incidence of T1D. By contrast, a deciency in cathepsin L imparted com-
plete resistance to the disease [95]. Cathepsin L-decient NOD mice are also CD4+
lymphopenic, and possess an altered ratio of regulatory to activated T cells [95]. Zhou
et al. have suggested that cathepsin G plays a crucial role in processing proinsulin
[96], one of the major autoantigens in T1D. Cathepsin G activity is higher in peripheral
blood mononuclear cells from T1D patients compared to controls and a cathepsin G
inhibitor reduced proinsulin-reactive T cell activation.
In summary, changes in the activities of lysosomal proteases may result in impaired
phago- or endocytosis, inadequate extracellular matrix turnover, and remodeling. is
point towards the involvement of lysosomal enzymes in the pathogenesis of autoim-
mune diseases. eir roles in these diseases are not yet fully understood, but further
study of their signicance could point towards new approaches for treatment of these
diseases.
ACKNOWLEDGEMENTS
W. Ge. and Y.-P. Gao are supported by National Natural Science Foundation of China
(81373150). All authors declare that there is no conict of interest.
Declaration of Interest
e authors report no conict of interest. e authors alone are responsible for the
content and writing of the article.
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