Mechanisms and pathways of innate immune activation and regulation in health and cancer

Abstract

Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer.

Keywords: AIM2, absent in melanoma 2; ALRs, AIM2-like receptors; AMPK, AMP activated protein kinase; ASC, apoptosis-associated speck-like protein containing a CARD; Atg16L, autophagy related 16-like; BMM, bone marrow-derived macrophage; CARD, caspase recruitment domain; CDNs, cyclic dinucleotides; CLRs, C-type lectin receptors; CMV, cytomegalovirus; CYLD, the familial cylindromatosis tumor suppressor gene; DAMPs, danger-associated molecular patterns; DCs, dendritic cells; DDX41, DEAD (Asp-Glu-Ala-Asp) box polypeptide 41; ER, endoplasmic reticulum; GBP5, guanylate-binding protein 5; GSK3β, Glycogen synthase kinase 3β; HCC, hepatocellular carcinoma; IFI16, interferon, gamma-inducible protein 16; IFN, interferon; IKK, IkB kinase; IKKi, inducible IkB kinase; IRAK, interleukin-1 receptor-associated kinase; IRF, interferon regulatory factor; KSHV, Kaposi's sarcoma-associated herpesvirus; LBP, LPS-binding protein; LGP 2, laboratory of genetics and physiology 2; LPS, lipopolysaccharide; LRR, leucine-rich repeat; LT, lethal toxin; LUBAC, linear ubiquitin assembly complex; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated protein 5; MDP, muramyl dipeptide; MIB, mind bomb; MyD88, myeloid differentiation factor 88; NAIPs, neuronal apoptosis inhibitory proteins; NEMO, NF-kB essential modulator; NLRs, Nod- like receptors; NOD, nucleotide-binding oligomerization domain; Nrdp1, neuregulin receptor degradation protein 1; PAMPs, pathogen-associated molecular patterns; PKC-d, protein kinase C delta; PKR, dsRNA-dependent protein kinase; PRRs; PRRs, pathogen recognition receptors; RACK1, receptor for activated C kinase 1; RAUL, RTA-associated E3 ligase; RIG-I, retinoic acid-inducible gene 1; RIP, receptor-interacting protein; RLRs, RIG-I-like receptors; ROS, reactive oxygen species; SARM, sterile a- and armadillo motif-containing protein; SIGIRR, single Ig IL-1-related receptor; SOCS, suppressor of cytokine signaling; STING, stimulator of interferon gene; TAK1, TGF-b-activating kinase 1; TANK, TRAF family-member-associated NF-kB activator; TBK1, TANK binding kinase 1; TIR, Toll IL-1 receptor; TIRAP, TIR domain-containing adapter protein; TLRs, Toll-like receptors; TRAF, TNFR-associated factor; TRAILR, tumor-necrosis factor-related apoptosis-inducing ligand receptor; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain-containing adaptor inducing IFN-b; TRIMs, tripartite motif containing proteins; TRIP, TRAF-interacting protein; ULK1, autophagy related serine threonine UNC-51- like kinase; cDC, conventional dendritic cell; cGAS, cyclic GMP-AMP synthase; cIAP, cellular inhibitor of apoptosis protein; cancer; iE-DAP, g-D-glutamyl-meso-diaminopimelic acid; inflammation; innate immunity; pDC, plasmacytoid dendritic cell; type I interferon.

Figure 1.

A schematic representation of TLR signaling pathways. TLRs are activated by ligand binding, which leads to dimerization of TLRs and to recruitment of TLR domain-containing adaptor proteins. Next, MyD88/IRAK1/IRAK4 or TRIF activates TRAF6, which, in turn, catalyzes the formation of a K63-linked polyubiquitin chain on TRAF6, itself. The polyubiquitin chain acts as the scaffold, recruiting TAK1 and its binding proteins, which leads to IKK-α/β activation. Activated IKKα/β specifically phosphorylates IkBα, resulting in IkBα degradation and NF-kB translocation into the nucleus. TRIF can also recruit TRAF3 to activate TBK1 and IKKi. TBK1/IKKi directly phosphorylates IRF3/7 to activate type I IFN signaling pathways. Various molecules positively (green arrow) or negatively (red blunt arrow) regulate TLR-induced signaling pathways.

Figure 2.

Activation and regulation of inflammasomes. The identified core components of inflammasomes belong to 2 families: (1) the NLR family (such as NLRP1b, NLRP3 and NLRC4); (2) the PYHIN (PYD and HIN200 domain-containing protein) family (such as AIM2). NLRs or AIM2, together with ASC, activate caspase-1, leading to downstream effector functions such as pyroptosis and processing of pro-IL-1β and pro-IL-18. Multiple regulators exert rigorous control on these pathways through their positive (green arrow) or negative (red blunt arrow) regulation. CARD, caspase recruitment domain; FIIND, domain with function to find; LRR, leucine-rich repeat; NACHT, nucleotide binding and oligomerization domain; NLR, Nod-like receptor; PYD, pyrin; HIN200, haematopoietic interferon-inducible nuclear antigens with 200 amino-acid repeats.

Figure 3.

A schematic representation of cytosolic RNA and DNA-induced type I IFN signaling pathway and its regulators. RIG-I and MDA5 recognize different groups of viral RNAs and initiate signaling cascades that begin with prion-like polymerization of MAVS. MAVS recruits and activates TRAF2, TRAF3, TRAF5, and TRAF6. Polyubiquitin chains on these ligases are sensed by NEMO through its ubiquitin-binding domains, in turn, recruiting IKK and TBK1 complexes to phosphorylate IκBα and IRF3, respectively. LGP2 may function as a regulator to modulate the activity of RIG-I and MDA5. Viral DNA could activate cGAS and other DNA sensors, which are all proposed to transduce signals to the ER-localized adaptor protein STING. STING triggers TBK1‑dependent type I IFN response. RNA polymerase III transcribes the DNA into 5'ppp-RNA, which triggers the RIG-I pathway. Most of the key molecules involved in the RNA- and DNA-sensing pathways can be targeted by E3 ligases, deubiquitinases or regulatory NLRs, which negatively (red blunt arrow) or positively (green arrow) regulate type I IFN responses.