The multifunctional roles of autophagy in the innate immune response: Implications for regulation of transplantation rejection

Abstract

Organ transplantation is the main treatment for end-stage organ failure, which has rescued tens of thousands of lives. Immune rejection is the main factor affecting the survival of transplanted organs. How to suppress immune rejection is an important goal of transplantation research. A graft first triggers innate immune responses, leading to graft inflammation, tissue injury and cell death, followed by adaptive immune activation. At present, the importance of innate immunity in graft rejection is poorly understood. Autophagy, an evolutionarily conserved intracellular degradation system, is proven to be involved in regulating innate immune response following graft transplants. Moreover, there is evidence indicating that autophagy can regulate graft dysfunction. Although the specific mechanism by which autophagy affects graft rejection remains unclear, autophagy is involved in innate immune signal transduction, inflammatory response, and various forms of cell death after organ transplantation. This review summarizes how autophagy regulates these processes and proposes potential targets for alleviating immune rejection.

Keywords: autophagy; cell death; graft rejection; innate immune response; organ transplantation; oxidative stress.

FIGURE 1

Schematic diagram of the interplay between autophagy and PRRs (including their downstream signalling molecules) in organ transplantation. All kinds of PAMPs/DAMPs can be recognized by PRRs, activating their downstream signalling pathway following organ transplantation. (1) PAMPs/DAMPs directly bind to TLRs and activate the MyD88-TRAF6 and TRIF pathways. Activation of TRAF6 induces the K63-linked polyubiquitination of Beclin-1, promoting autophagy degradation by enhancing PI3KC activity. In addition, the interaction between Beclin-1 and MyD88/TRIF induces the dissociation of Beclin-1 and Bcl-2, leading to autophagy initiation. (2) Activation of NOD1 by reperfusion contributes to autophagic degradation via the interaction with ATG16L1 and ATG5. (3) On one hand, the expression of RIG-I decreases SQSTM1 and boosts autophagic degradation. On the other hand, activation of RIG-I triggers autophagy via the MAVS-TRAF6-Beclin-1 signalling axis.

FIGURE 2

Interrelations between autophagy and cell death in organ transplantation. Schematic shows the key signalling molecules and signalling pathways. (1) NF-κB, MAPK, FOXO3, mTOR and Beclin-1-Bcl2 are involved in autophagy-regulated apoptosis. (2) RIPK1, RIPK3. mTOR and AMPK are involved in autophagy-regulated necroptosis. (3) ATG5/7, NCOA4, and CIRBP-ELAVL1-Beclin-1 axis are involved in autophagy-regulated ferroptosis. (4) NLRP3, mTOR and STING are involved in autophagy-regulated pyroptosis.