Figures & data
Figure 1. Role of autophagy in the maintenance of intestinal homeostasis and potential mechanisms by which defective autophagy may contribute to CD development. At the intestinal epithelium: (A) Autophagy modulates epithelial barrier function via lysosome-mediated degradation of CLDN2. Dysfunctional autophagy leads to increased CLDN2 level associated with increased intestinal permeability [Citation10,Citation11]. (B) Defective autophagy leads to intestinal dysbiosis and increased IgA-coated bacterial amount [Citation26,Citation27,Citation32]. (C) By promoting mitochondrial homeostasis, autophagy protects IECs from cell death and prevents loss of Paneth cells [Citation15,Citation16]. MIR346, induced under ER stress, enhances GSK3B translation, favoring the dissociation between BCL2 and BECN1. This consequently activates mitophagy, thus reducing ROS level [Citation41]. ROS-mediated NLRP3 inflammasome activation, which leads to CASP1 activation and subsequently IL18 and IL1B production, is also inhibited by EIF2AK4-induced mitophagy upon amino acid starvation [Citation63]. Dysfunctional autophagy leads to accumulation of damaged mitochondria and ROS, increasing inflammasome activation and inflammation [Citation63] and aggravating ROS-induced cell death [Citation41]. (D) NOD2 recruits ATG16L1 to the plasma membrane at the bacterial entry site, initiating autophagy. Association of IRGM with NOD2 promotes IRGM ubiquitination and the assembly of the core autophagy machinery, promoting xenophagy [Citation76]. Autophagy-associated risk variants induce defective autophagy and impaired intracellular bacterial clearance. (E) Stimulation of NOD and TNF receptors in IECs activates CHUK, which phosphorylates ATG16L1, leading to its stabilization, thus preventing ER stress during inflammation. Inactivation of CHUK fails to stabilize ATG16L1, which is consequently degraded by CASP3, increasing ER stress [Citation47]. (F) In Paneth cells, NOD2 activation in response to commensal bacteria leads to recruitment of LRRK2, RIPK2 and RAB2A to dense core vesicles, a process required for sorting and secretion of lysozyme and other antimicrobial peptides. Dysfunctional NOD2 or LRRK2 result in lysosome-mediated degradation of lysozyme [Citation21,Citation22]. (G) During infection of Paneth cells with invasive bacteria, ER-Golgi secretion pathway is impaired, lysozyme is secreted via secretory autophagy. This process requires ER stress-mediated EIF2AK3-EIF2A activation in Paneth cells and activation of TLR-MYD88 in DCs that promotes IL22 secretion by type 3 innate lymphoid cells. Paneth cells with defective autophagy fails to secrete lysozyme via secretory autophagy [Citation23]. (H) During ER stress in Paneth cells, ERN1 is recruited to autophagosomes via its interaction with OPTN, thus being degraded by autophagy. Impaired clearance of ERN1 aggregates during ER stress due to defective autophagy leads to increased ER stress and spontaneous CD-like transmural ileitis in mice [Citation44]. (I) In intestinal stem cells, autophagy limits ROS accumulation that inhibits their differentiation, allowing epithelium regeneration. Defective autophagy leads to ROS accumulation and impaired epithelium regeneration [Citation57]. (J) In macrophages, in response to TLR4 activation, which drives TIRAP-dependent inflammation, autophagy is activated to control TIRAP turnover and to limit production of IFNB1. Defective autophagy leads to TIRAP accumulation and subsequently increased IFNB1 production [Citation83]. In response to TLR4 activation, NFKB activates expression of NLRP3, pro-IL1B and SQSTM1 [Citation67]. SQSTM1 promotes mitophagy to prevent NLRP3 inflammasome activation, thus inhibiting IL1B production [Citation67]. IRGM also limits NLRP3 inflammasome activation by preventing its assembly and by mediating selective autophagic degradation of the inflammasome components [Citation68]. Defective autophagy leads to accumulation of dysfunctional mitochondria and ROS, enhancing NLRP3 inflammasome activation and subsequently IL1B production. (K) In DCs, autophagy degrades intracellular pathogens and participates in the presentation of antigens to T cells to induce adaptive immune responses. EIF2AK4-induced mitophagy inhibits ROS-mediated NLRP3 inflammasome activation, decreasing IL18 and IL1B production [Citation63]. Defective autophagy leads to impaired bacterial elimination and antigen presentation, impairing T cell activation [Citation92]. T cell activation is supported by the autophagic receptor TAX1BP1 that binds to LC3 and induces autophagy, providing critical amino acids that activates MTORC1 complex and induces metabolic transition of activated T cells [Citation99]. An alteration of autophagy impairs T cell metabolic transition and proliferation, leading to decreased numbers of CD4+ and CD8+ T cells, impaired memory CD8+ T cell development, decreased Treg cell survival and increased Th2 and Th17 responses [Citation91,Citation93–Citation99]. (L) Bacteroides fragilis from gut microbiota secrete immunomodulatory molecules through OMVs that are recognized by DCs via TLR2, activating LAP through NOD2 and ATG16L1 and inducing FOXP3+ Treg cells, which produce IL10, thus limiting CD4+ T cell-mediated inflammatory responses [Citation101,Citation102]. DCs having the autophagy-related risk variants fail to induce IL10 production by FOXP3+ Treg cells in response to B. fragilis-derived OMVs [Citation101,Citation102].
![Figure 1. Role of autophagy in the maintenance of intestinal homeostasis and potential mechanisms by which defective autophagy may contribute to CD development. At the intestinal epithelium: (A) Autophagy modulates epithelial barrier function via lysosome-mediated degradation of CLDN2. Dysfunctional autophagy leads to increased CLDN2 level associated with increased intestinal permeability [Citation10,Citation11]. (B) Defective autophagy leads to intestinal dysbiosis and increased IgA-coated bacterial amount [Citation26,Citation27,Citation32]. (C) By promoting mitochondrial homeostasis, autophagy protects IECs from cell death and prevents loss of Paneth cells [Citation15,Citation16]. MIR346, induced under ER stress, enhances GSK3B translation, favoring the dissociation between BCL2 and BECN1. This consequently activates mitophagy, thus reducing ROS level [Citation41]. ROS-mediated NLRP3 inflammasome activation, which leads to CASP1 activation and subsequently IL18 and IL1B production, is also inhibited by EIF2AK4-induced mitophagy upon amino acid starvation [Citation63]. Dysfunctional autophagy leads to accumulation of damaged mitochondria and ROS, increasing inflammasome activation and inflammation [Citation63] and aggravating ROS-induced cell death [Citation41]. (D) NOD2 recruits ATG16L1 to the plasma membrane at the bacterial entry site, initiating autophagy. Association of IRGM with NOD2 promotes IRGM ubiquitination and the assembly of the core autophagy machinery, promoting xenophagy [Citation76]. Autophagy-associated risk variants induce defective autophagy and impaired intracellular bacterial clearance. (E) Stimulation of NOD and TNF receptors in IECs activates CHUK, which phosphorylates ATG16L1, leading to its stabilization, thus preventing ER stress during inflammation. Inactivation of CHUK fails to stabilize ATG16L1, which is consequently degraded by CASP3, increasing ER stress [Citation47]. (F) In Paneth cells, NOD2 activation in response to commensal bacteria leads to recruitment of LRRK2, RIPK2 and RAB2A to dense core vesicles, a process required for sorting and secretion of lysozyme and other antimicrobial peptides. Dysfunctional NOD2 or LRRK2 result in lysosome-mediated degradation of lysozyme [Citation21,Citation22]. (G) During infection of Paneth cells with invasive bacteria, ER-Golgi secretion pathway is impaired, lysozyme is secreted via secretory autophagy. This process requires ER stress-mediated EIF2AK3-EIF2A activation in Paneth cells and activation of TLR-MYD88 in DCs that promotes IL22 secretion by type 3 innate lymphoid cells. Paneth cells with defective autophagy fails to secrete lysozyme via secretory autophagy [Citation23]. (H) During ER stress in Paneth cells, ERN1 is recruited to autophagosomes via its interaction with OPTN, thus being degraded by autophagy. Impaired clearance of ERN1 aggregates during ER stress due to defective autophagy leads to increased ER stress and spontaneous CD-like transmural ileitis in mice [Citation44]. (I) In intestinal stem cells, autophagy limits ROS accumulation that inhibits their differentiation, allowing epithelium regeneration. Defective autophagy leads to ROS accumulation and impaired epithelium regeneration [Citation57]. (J) In macrophages, in response to TLR4 activation, which drives TIRAP-dependent inflammation, autophagy is activated to control TIRAP turnover and to limit production of IFNB1. Defective autophagy leads to TIRAP accumulation and subsequently increased IFNB1 production [Citation83]. In response to TLR4 activation, NFKB activates expression of NLRP3, pro-IL1B and SQSTM1 [Citation67]. SQSTM1 promotes mitophagy to prevent NLRP3 inflammasome activation, thus inhibiting IL1B production [Citation67]. IRGM also limits NLRP3 inflammasome activation by preventing its assembly and by mediating selective autophagic degradation of the inflammasome components [Citation68]. Defective autophagy leads to accumulation of dysfunctional mitochondria and ROS, enhancing NLRP3 inflammasome activation and subsequently IL1B production. (K) In DCs, autophagy degrades intracellular pathogens and participates in the presentation of antigens to T cells to induce adaptive immune responses. EIF2AK4-induced mitophagy inhibits ROS-mediated NLRP3 inflammasome activation, decreasing IL18 and IL1B production [Citation63]. Defective autophagy leads to impaired bacterial elimination and antigen presentation, impairing T cell activation [Citation92]. T cell activation is supported by the autophagic receptor TAX1BP1 that binds to LC3 and induces autophagy, providing critical amino acids that activates MTORC1 complex and induces metabolic transition of activated T cells [Citation99]. An alteration of autophagy impairs T cell metabolic transition and proliferation, leading to decreased numbers of CD4+ and CD8+ T cells, impaired memory CD8+ T cell development, decreased Treg cell survival and increased Th2 and Th17 responses [Citation91,Citation93–Citation99]. (L) Bacteroides fragilis from gut microbiota secrete immunomodulatory molecules through OMVs that are recognized by DCs via TLR2, activating LAP through NOD2 and ATG16L1 and inducing FOXP3+ Treg cells, which produce IL10, thus limiting CD4+ T cell-mediated inflammatory responses [Citation101,Citation102]. DCs having the autophagy-related risk variants fail to induce IL10 production by FOXP3+ Treg cells in response to B. fragilis-derived OMVs [Citation101,Citation102].](/cms/asset/357a9d27-8781-45aa-bd78-793ac98de8f5/kaup_a_1635384_f0001_c.jpg)