New insight in treating autoimmune diseases by targeting autophagy

Figures & data

Figure 1. Illustration of the three types of autophagy. (a) In the macroautophagy process, abnormally aggregated protein and microbes are recruited to phagophore, and then phagophore can prolong and enclose to form autophagosomes, and finally the autophagosomes fuse with lysosomes for degradation. (b) In chaperone-mediated autophagy (CMA), proteins containing KFERQ motif keep unfolding with the help of chaperone, and bind to LAMP2A on lysosomes. Proteins translocate from cytosol through LAMP2A into lysosomes lumen one by one. (c) In microautophagy, invagination of lysosome membranes directly engulfs cargoes for degradation.

Figure 2. ATGs involve different diseases. ATGs are significant to regulate autophagy process, while they also involve in the occurrence and progression of various diseases, such as breast cancer, Parkison’s disease, lung cancer and so on.

Table 1. Macroautophagy and CMA in autoimmune diseases.

The forms of autophagy	Diseases	Mechanism	References
Macroautophagy (referred as autophagy)	SLE	LRRK2 has a strongly positive correlation with disease severity. LRRK2 deficiency attenuates pristane-induced lupus-like pathology in mice possibly through regulating B cell terminal differentiation and subsequent antibody production.	[55]
		Blocking the activation of mTOR signalling induces autophagy and corrects the functions of T cells to improve SLE.	[56]
	RA	Aberrant autophagy induces the hyperactivation of T cells and the resistance of apoptosis aggravating RA.	[57]
		OPTN plays a protective role in RA upregulated in the presence of proinflammatory cytokines in FLS.	[58]
	MS	Autophagy failure affects OL functions inducing MS under the prolong stress.	[59]
		ATG7 deficiency in microglia leads to an increase in intracellular accumulation of phagocytosed myelin and progressive MS-like disease.	[60]
	IBD	IRGM can block inflammasome assembly and mediate the autophagic degradation of NLRP3. It means that IRGM is protective from inflammatory disorders.	[61]
		Autophagy can enhance TJ barrier to maintain the integrity of barrier.	[62]
	Psoriasis	Autophagic degradation of innate immune sensors like cGAS, RIG-I and TLR3 inhibits synthesis of proinflammation cytokines to relieve psoriasis.	[63]
		PSORI-CM02 induces autophagy and then inhibits the proliferation of HaCaT cells to alleviate psoriasis in vivo and in vitro via suppression of the PI3K/Akt/mTOR pathway.	[64,65]
	Vitiligo	Autophagy-related TNFSF10/ hsa-let-7a-5p axis regulates the development of vitiligo by autophagy and apoptosis.	[66]
		HSF1-ATG5/12 axis can prevent oxidative stress-induced melanocyte death.	[67]
CMA	SLE	It is found that CMA is upregulated in MRL/lpr lupus-prone mice. And using P140 phosphopeptide to inhibit CMA can lower activation of autoreactive T cells and relieve lupus symptoms.	[68]
	Sjögren’s syndrome	Using P140, which acts on CMA, can rescue MRL/lpr mice from cellular infiltration and autophagy defects occurring in salivary glands. It is suggested that targeting CMA might therapy Sjögren’s syndrome.	[69]
	Type 1 diabetes	PFK-2 can be degraded by UPS and CMA. The loss of PFK-2 impaired the capacity to dynamically regulate glycolysis and elevates the levels of early glycolytic intermediates. It means a pathological impairment in type 1 diabetes.	[70]

Table 2. Treatment strategies against autoimmune diseases by modulating autophagy.

Treatment strategies	Autoimmune diseases	Targets	References
HCQ and CQ	SLE; RA	HCQ and CQ interfere the presentation of self-antigen, and inhibit the degradation of autophagic cargoes.	[167,168]
	MS	CQ blocks the integration of autophagosome and lysosome.	[169]
ISD017	SLE	ISD170 blocks STING trafficking through STIM1.	[170]
Tocilizumab	SLE	Tocilizumab restores autophagy process, and reverses the accumulation of p62 in the SLE patients’ macrophages.	[171]
Empagliflozin	SLE	Empagliflozin reduces the activity of mTORC1, and relieve the symptoms of lupus nephritis.	[172]
SSTC3	SLE	SSTC3 activates CSNK1A1/CK1α to increase p62-mediated STING degradation.	[97]
P140	SLE	P140 affects refolding properties of HCS70, and increases the accumulation of p62 and LC3 to impact presentation of self-antigens and the activation of T cells.	[173,174]
	IBD	P140 can correct autophagy defects in IBD mice model.	[175]
Quercetin	RA	Quercetin inhibits neutrophil extracellular traps (NET) formation that is associated with the pathogenesis of RA by suppressing autophagy.	[176]
Chelerythrine	RA	Chelerythrine increases the intracellular level of ROS and the apoptotic rate of HFLS-RA by activating the AMPK/mTOR/ULK-1 signalling pathways.	[177]
Celastrol	RA	Celastrol increases the level of autophagosome and the expression of LC3B via inhibiting PI3K/AKT/mTOR signalling pathway.	[112]
Resveratrol	RA	Resveratrol can relieve experimental RA by activating autophagy.	[114]
Anti-TNFα therapy (such as infliximab, adalimumab and golimumab)	RA; IBD	Anti-TNFα antibodies induce regulatory macrophages transform into a phenotype similar to M2, and this progress is tightly related to autophagy.	[178]
Dimethyl fumarate	MS	Dimethyl fumarate treatment increases the expression of LC3 and ATG7 to suppress proinflammatory responses and protect neurons in microglia.	[179]
Haloperidol; clozapine	MS	Haloperidol and clozapine inhibit autophagy, prevent demylinization, induce remyelination, and revert MS behavioural deficits.	[180]
Sildenafil	MS	Sildenafil alleviates EAE by activating autophagy in the spinal cord, by means of the eNOS-NO-AMPK-mTOR-LC3-beclin1-ATG5 and eNOS-NO-AMPK-mTOR-CREB BDNF pathways.	[181]
Nicotinamide adenine dinucleotide	MS	Nicotinamide adenine dinucleotide alleviates EAE through the activation of autophagy and the suppression of NLRP3 inflammasome.	[182]
Dapagliflozin	IBD	Dapagliflozin activates autophagy and suppresses apoptosis to attenuate experimental inflammatory bowel disease in rats through AMPK/mTOR, HMGB1/RAGE and Nrf2/HO-1 pathways.	[183]
Andrographolide	IBD	Andrographolide can prevent colitis-associated cancer via mitophagy-mediated NLRP3 inflammasome inhibition.	[184]
Agonist of cannabinoid receptor 2	IBD	Agonist of cannabinoid receptor 2 inhibits NLRP3 inflammasome activation and alleviates DSS-induced colitis in mice through promoting autophagy process.	[185]
AC-73	IBD	AC-73 inhibits CD147/ERK1/2 and STAT3 signalling pathway activation and induces autophagy.	[186]
Atrial Natriuretic Peptide (ANP)	IBD	ANP can repair the gut barrier and inhibit ER stress-induced autophagy via the STING pathway.	[187]
Cis-khellactone	Psoriasis	Cis-khellactone suppresses proinflammatory phenotypic macrophages by promoting autophagy.	[188]
Jueyin granules	Psoriasis	Jueyin granules induce autophagy by upregulating ApoA1 and inhibit the infiltration of CD4+ T cells and macrophages to alleviate imiquimod-induced psoriatic inflammation in a mouse model.	[148,189]
PSORI-CM02	Psoriasis	PSORI-CM02 induces autophagy and then inhibits the proliferation of HaCaT cells to alleviate psoriasis in vivo and in vitro via suppression of the PI3K/Akt/mTOR pathway.	[64]
Fenofibrate	Psoriasis	Fenofibrate blocks IL-17A signalling and enhance autophagy process inducing anti-inflammatory effects.	[190]
Epigallocatechin-3-gallate (EGCG)	Vitiligo	EGCG induces autophagy and apoptosis to treat vitiligo via targeting TNFSF10.	[66]
Itaconate	AIH	Itaconate can decrease DCs autophagy and maturation to ameliorates liver inflammation through regulating the PI3K/AKT/mTOR pathway.	[191]
Methylprednisolone	AIH	Methylprednisolone ameliorated mitochondria-mediated apoptosis and autophagy dysfunction through the Akt/mTOR signalling pathway.	[192]
Astaxanthin	AIH	Astaxanthin reduced immune liver injury through downregulation of JNK/p-JNK-mediated apoptosis and autophagy.	[193]
Neuregulin-4	T1D	Neuregulin-4 can promote autophagy in T1D mice via the AMPK/mTOR signalling pathway.	[157]
Allicin	T1D	Allicin can activate AMPK/mTOR mediated autophagy pathway to suppress T1D.	[194]
Vitamin D	T1D	Vitamin D can increase autophagy process to prevent T1D.	[195]

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