Human TLR10 is an anti-inflammatory pattern-recognition receptor

Abstract

Toll-like receptor (TLR)10 is the only pattern-recognition receptor without known ligand specificity and biological function. We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects. Blocking TLR10 by antagonistic antibodies enhanced proinflammatory cytokine production, including IL-1β, specifically after exposure to TLR2 ligands. Blocking TLR10 after stimulation of peripheral blood mononuclear cells with pam3CSK4 (Pam3Cys) led to production of 2,065 ± 106 pg/mL IL-1β (mean ± SEM) in comparison with 1,043 ± 51 pg/mL IL-1β after addition of nonspecific IgG antibodies. Several mechanisms mediate the modulatory effects of TLR10: on the one hand, cotransfection in human cell lines showed that TLR10 acts as an inhibitory receptor when forming heterodimers with TLR2; on the other hand, cross-linking experiments showed specific induction of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra, 16 ± 1.7 ng/mL, mean ± SEM). After cross-linking anti-TLR10 antibody, no production of IL-1β and other proinflammatory cytokines could be found. Furthermore, individuals bearing TLR10 polymorphisms displayed an increased capacity to produce IL-1β, TNF-α, and IL-6 upon ligation of TLR2, in a gene-dose-dependent manner. The modulatory effects of TLR10 are complex, involving at least several mechanisms: there is competition for ligands or for the formation of heterodimer receptors with TLR2, as well as PI3K/Aktmediated induction of the anti-inflammatory cytokine IL-1Ra. Finally, transgenic mice expressing human TLR10 produced fewer cytokines when challenged with a TLR2 agonist. In conclusion, to our knowledge we demonstrate for the first time that TLR10 is a modulatory pattern-recognition receptor with mainly inhibitory properties.ighly conserved molecular structures of invading microorganisms are recognized by immune cells through patternrecognition receptors, of which Toll-like receptors (TLRs) are the most documented family. In humans, 10 members of the TLR family have been described (1). In general, specific ligation of TLRs leads to induction of proinflammatory mediators, such as cytokines and chemokines. One member of the TLR family however, TLR10, is considered an orphan receptor because of its still-unknown ligands and function.Human TLR10 is encoded on chromosome 4 within the TLR2 gene cluster, together with TLR1, TLR2, and TLR6, and shares all structural characteristics of the TLR family (2, 3). However, TLR10 differs from other TLRs by its lack of a classic downstream signaling pathway (4), despite its interaction with the myeloid differentiation primary response gene 88 adaptor protein (3). TLR10 is predominantly expressed in tissues rich in immune cells, such as spleen, lymph node, thymus, tonsil, and lung (2). Expression of TLR10 can be induced in B cells, dendritic cells, eosinophils, and neutrophils (3, 5, 6), as well as on nonimmune cells, such as trophoblasts (7). TLR1 and TLR6 are known to form heterodimers with TLR2, and this was shown for TLR10 as well (3,8). It is therefore ...

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

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“…Second, acting on the vascular and lymphatic system Type-I-IFNs inhibit angiogenesis through VEGF downregulation (9). Finally, acting on the immune system Type-I-IFNs may favor tumor regression by stimulating the maturation of DCs (10), promoting the release of pro-inflammatory cytokines (11), favoring CTL cross-priming (12), fostering the activation and survival of CD8 C and CD4 C T cells (13) and of NK cells (14), having a crucial role on core energetic metabolism regulation (15), and negatively regulating immune suppressive Treg cells (16) and MDSCs (17). CSC: cancer stem cell; DC: dendritic cell; EMT: epithelial-to-mesenchymal transition; IFNs: interferons; MDSC: myeloid-derived suppressor cell; MHC-I: major histocompatibility complex-I; NK: natural killer; PD1: programmed death 1; PD-L1: programmed death-ligand 1; TAAs: tumor-associated antigens; TCA: tricarboxylic acid; Treg: regulatory T cell; VEGF: vascular endothelial growth factor; VLS: vascular and lymphatic system.…”

Genetic Variation in Pattern Recognition Receptors: Functional Consequences and Susceptibility to Infectious Disease

“…Recent studies have suggested that the function of TLR10 differs from other TLRs, as it was shown to inhibit TLR2-driven innate immune activation [68][69][70]. By contrast, TLR10 has also been described as a stimulatory receptor in the innate immune recognition [ TLR6 sequence variant rs5743810 (Pro249Ser) leads to the substitution of proline for serine at amino-acid position 249 of the TLR6 protein.…”

“…TLR6 sequence variant rs5743810 is associated with susceptibility to tuberculosis [16], complicated skin and skin structure infections [22], aspergillosis [23] and malaria [20]. [69][70]78]. How these TLR10 sequence variants precisely exert their effect remains unknown, but the location of rs4129009 in the LRR region and rs11096955 in the TIR domain could indicate involvement in the recognition of PAMPs or signal transduction, respectively.…”

Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword

“…2009), Grimm et al (2010), Hasan et al (2005), Hornung et al (2002), Huen and Rook(2014),Nagase et al (2003),Oosting et al (2014) …”