Toll‐like receptors’ two‐edged sword: when immunity meets apoptosis

Abstract

Toll‐like receptors (TLR) have emerged as key players in the detection of pathogens and the induction of anti‐microbial immune response. TLR recognize pathogen‐associated molecular patterns, and trigger anti‐microbial innate immune responses ranging from the secretion of pro‐inflammatory mediators to the increase of natural killer cell cytotoxicity. Besides activating the innate immune response, TLR engagement also shapes the adaptive immune response. Indeed, the broad diversity of signaling pathways initiated by TLR is progressively unraveled. Recent reports suggested that among the anti‐microbial defenses they initiate, members of the TLR family can induce apoptosis. This review focuses on this newly described function of TLR, and emphasizes the similarities and differences between the different apoptosis‐signaling pathways described downstream of TLR. The functional relevance of TLR‐triggered apoptosis is also discussed, as therapeutic applications are likely to ensue in the near future.

dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8

“…However, contrary to TNFRI, caspase-8 appears to be physically linked to TLR3 through TRIF/RIP1. Given that other TLRs are also able to trigger apoptosis, 38 and that caspase-8 has also non-apoptotic functions, 39 it is tempting to speculate that related platforms may assemble upon stimulation of these TLRs, for the triggering of apoptosis, but also for the regulation of non-apoptotic signaling activities. Further studies will be required to fully address these questions.…”

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

“…Inhibition of NF-κB has been reported to abrogate prosurvival signals within cells and to augment Pam 3 CSK 4 -induced cell death in THP-1 cells, supporting that NF-κB-regulated survival signals are important to suppress the full extent of TLR2-mediated cell death [41,75]. Likewise, abrogating TLR2/PI3K/Akt-dependent mechanisms by inhibition with LY294002 failed to protect cardiomyocytes against doxorubicin-induced cardiomyopathy [83] and brain cells against ischemic injury [84].…”

“…The differential activation of the adaptor protein Mal by TLR2/6 ligand Pam 2 CSK 4 may account for the divergent signaling kinetics of both NF-kB and PI3K activation. While NF-κB is generally regarded as an anti-apoptotic transcription factor [74], depending on the inducing stimulus and cell context, NF-κB can also behave in a proapoptotic fashion [68,[74][75][76][77][78]. Likewise, the PI3 kinase pathway is an established key regulator of cell proliferation and survival that can also regulate apoptosis induction [79].…”

“…Likewise, the PI3 kinase pathway is an established key regulator of cell proliferation and survival that can also regulate apoptosis induction [79]. Previous studies have revealed that variations in NF-κB activation kinetics affect outcome by influencing target gene selection [80][81][82], resulting in quantitative and qualitative regulation of gene expression [81], as well as leading to marked differences in the magnitude of IL-12p40 secretion following stimulation with either LPS, Pam 3 CSK 4 , or CpG oligonucleotides [82], and failed leukocyte recruitment by lipoteichoic acid [27].Inhibition of NF-κB has been reported to abrogate prosurvival signals within cells and to augment Pam 3 CSK 4 -induced cell death in THP-1 cells, supporting that NF-κB-regulated survival signals are important to suppress the full extent of TLR2-mediated cell death [41,75]. Likewise, abrogating TLR2/PI3K/Akt-dependent mechanisms by inhibition with LY294002 failed to protect cardiomyocytes against doxorubicin-induced cardiomyopathy [83] and brain cells against ischemic injury [84].…”

Relação entre o oncogene BCR-ABL e os receptores de tipo TOLL (TLR).

“…A ativação dos receptores de tipo Toll já foi relacionada tanto com o aumento da susceptibilidade quanto com a indução da resistência à morte por apoptose (Salaun et al, 2007). Com o intuito de alterar a alta resistência à apoptose descrito para as células expressando BCR-ABL (Bedi et al, 1994) Em neoplasias hematológicas foram demonstrados aspectos positivos e negativos da ativação desta sinalização e os primeiros estão sendo aproveitados para o combate de doenças como a Leucemia Linfocitica Crônica fazendo uso de agonistas dos receptores de TLR7 e 9 (Smits et al, 2010;Spaner e Masellis, 2007).…”