Research Highlights

Tuning TLR signals

Interferon (IFN)-γ modulates Toll-like receptor (TLR)-induced signaling and gene expression. In Immunity, Hu et al. find that IFN-γ inhibits cross-talk between TLR and Notch signals. In human macrophages, TLR stimulation induces expression of a subset of Notch target genes including HES1 and HEY1. TLR-triggered expression of HES1 and HEY1 occurs independently of new protein synthesis but requires basal activation of Notch signaling and the Notch effector protein RBP-J. IFN-γ suppresses this basal Notch signaling. TLR–Notch signal interplay has complex biological consequences. RBP-J enhances TLR-driven IL-6 production, whereas, in accordance with their established status as feedback inhibitors of Notch signaling, HES1 and HEY1 suppress TLR-triggered proinflammatory cytokine production. Thus, in macrophages, IFN-γ may relieve a Notch signal–mediated 'brake' on TLR signal transduction. CB

Immunity 29, 691–703 (2008)

Sharing signaling endosomes

Hematopoietic stem cells (HSCs) depend on stromal osteoblast cells to provide survival and differentiation signals in bone marrow niches. In Nature Cell Biology, Lippincott-Schwartz and colleagues show that HSCs adopt a highly polarized morphology that facilitates 'sharing' of signaling endosomes with the supporting osteoblast. HSC uropods enriched in membrane proteins VLA-4, CD63, CD81 and prominin 1 form at the contact interface. Active transfer of signaling molecules between HSCs and osteoblasts occurs at this interface, through a process distinct from degradative endocytosis or membrane fusion. Although the transfer mechanism remains to be deciphered, transfer of HSC-encoded signaling molecules induces osteoblasts to downregulate Smad2/3, which in turn upregulates expression of CXCL12, a chemokine known to support HSC homing and adhesion. Hence, intercellular cross-talk between HSCs and osteoblasts engenders positive feedback to maintain the stromal niche. LAD

Nat. Cell Biol. 11, 303–311 (2009)

Positive cross-talk by calcium

Cross-talk between Toll-like receptor signaling and other signaling pathways is common. In Blood, Cao and colleagues investigate whether the Ca²⁺–CaMKII pathway cross-talks with TLR signaling, as previous work has shown that lipopolysaccharide (LPS) can elicit Ca²⁺ flux in mouse macrophages. TLR3, 4 and 9 ligands could induce Ca²⁺ mobilization from internal Ca²⁺ stores and induce CaMKII-α phosphorylation. Blockade or knockdown of CaMKII attenuated, whereas overexpression of active CaMKII enhanced, TLR-induced proinflammatory cytokine and type I interferon production. CaMKII could phosphorylate TAK1, a MAPKKK essential for TLR-induced MAPK, NF-κB activation and proinflammatory cytokine production. In addition, CaMKII could phosphorylate the transcription factor IRF3, required for IFN-β production. Consistently, in vivo blockade of CaMKII activation lessened the severity of LPS-induced endotoxic shock. These data show that positive cross-talk with the Ca²⁺ signaling pathway is required for TLR responses in macrophages. JDKW

Blood 112, 4961–4970 (2008)

Tempering phagocytosis

Eicosanoid lipid mediators can suppress or enhance immune responses. In the Journal of Immunology, Lee et al. look at the combinatorial effects of suppressive prostaglandin E₂ (PGE₂) and activating leukotriene B₄ (LTB₄) or LTD₄ on alveolar macrophage phagocytic activities. PGE₂ signaling through Gα_s triggers increases in cyclic AMP concentration and suppression of phagocytosis and bactericidal activities, an effect that is counteracted by LTB₄ activation of Gα_i. FcγR-mediated phagocytosis leads to increased LTB₄ generation and further antagonizes PGE₂ suppression. LTD₄ has no effect on intracellular cAMP concentrations but synergizes with LTB₄ to increase phagocytosis in alveolar macrophages by inhibiting Rap-1 GTPase, a downstream effector of cAMP, through an unknown, cAMP-independent pathway. Future work should further illuminate how macrophages integrate opposing signals encountered in infected or inflamed tissues. LAD

J. Immunol. 182, 530–537 (2009)

IL-15 and NKG2D: dangerous synergy

Only in the presence of high concentrations of interleukin (IL)-15 or IL-2—such as those present in the intestines of patients with celiac disease—can NKG2D trigger cytotoxic T lymphocyte (CTL)-mediated cytolysis independently of T cell antigen receptor (TCR) stimulation. In the Journal of Experimental Medicine, Jabri and co-workers designate cytosolic phospholipase A2 (cPLA₂) activation a biologically relevant consequence of synergy between IL-15 and NKG2D signals. Inhibition or ablation of cPLA₂ suppresses cytotoxicity induced by stimulation with anti-NKG2D and high dose IL-2, or by NKG2D and TCR cross-linking. NKG2D-induced cPLA₂ phosphorylation requires Erk and Jnk but not p38 MAP kinases. IL-15 also induces phosphorylation of Erk, Jnk and cPLA₂, but the combination of IL-15 and anti-NKG2D triggers more robust cPLA₂ activity than either IL-15 or anti-NKG2D alone. A higher proportion of intraepithelial CTL expresses phosphorylated cPLA₂ in patients with celiac disease than in healthy individuals. CB

J. Exp. Med. doi:10.1084/jem.20071887 (23 February 2009)

Written by Christine Borowski, Laurie A. Dempsey & Jamie D.K. Wilson