Leishmania major parasites reside and multiply in late endosomal compartments of host phagocytic cells. Immune control of Leishmania growth absolutely requires expression of inducible Nitric Oxide Synthase (iNOS/NOS2) and subsequent production of NO. Here, we show that CD11b+ CD11c+ Ly-6C+ MHC-II+ cells are the main iNOS-producing cells in the footpad lesion and in the draining lymph node of Leishmania major-infected C57BL/6 mice. These cells are phenotypically similar to iNOS-producing inflammatory DC (iNOS-DC) observed in the mouse models of Listeria monocytogenes and Brucella melitensis infection. The use of DsRed-expressing parasites demonstrated that these iNOS-producing cells are the major infected population in the lesions and the draining lymph nodes. Analysis of various genetically deficient mouse strains revealed the requirement of CCR2 expression for the recruitment of iNOS-DC in the draining lymph nodes, whereas their activation is strongly dependent on CD40, IL-12, IFN-γ and MyD88 molecules with a partial contribution of TNF-α and TLR9. In contrast, STAT-6 deficiency enhanced iNOS-DC recruitment and activation in susceptible BALB/c mice, demonstrating a key role for IL-4 and IL-13 as negative regulators. Taken together, our results suggest that iNOS-DC represent a major class of Th1-regulated effector cell population and constitute the most frequent infected cell type during chronic Leishmania major infection phase of C57BL/6 resistant mice.
Innate immunity is the first line of defense against invading pathogens. A family of Toll-like receptors (TLRs) acts as primary sensors that detect a wide variety of microbial components and elicit innate immune responses. All TLR signaling pathways culminate in activation of the transcription factor nuclear factor-kappaB (NF-kB), which controls the expression of an array of inflammatory cytokine genes. NF-kB activation requires the phosphorylation and degradation of inhibitory kB (IkB) proteins, which is triggered by two kinases, IkB kinase a (IKKa) and IKKb. In addition, several TLRs activate alternative pathways involving the IKK-related kinases TBK1 [TRAF family member-associated NF-kB activator (TANK) binding kinase-1] and IKKi, which elicit antiviral innate immune responses. Here, we review recent progress in our understanding of the role of NF-kB in TLR signaling pathways and discuss potential implications for molecular medicine.
Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing specific patterns of microbial components. TLR signaling pathways arise from intracytoplasmic TIR domains, which are conserved among all TLRs. Recent accumulating evidence has demonstrated that TIR domain-containing adaptors, such as MyD88, TIRAP, and TRIF, modulate TLR signaling pathways. MyD88 is essential for the induction of inflammatory cytokines triggered by all TLRs. TIRAP is specifically involved in the MyD88-dependent pathway via TLR2 and TLR4, whereas TRIF is implicated in the TLR3- and TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors provide specificity of TLR signaling.
The family of Toll-like receptors (TLR1-TLR11) provides host defense in mammals by inducing proinflammatory innate immune response upon recognition of conserved structural component in pathogens. TLR mediated activation of signaling pathways that induce the expression of proinflammatory molecules is one of the well-studied but ever expanding fields of immunology. As a result, a wealth of information has been obtained which includes the identification of specific ligands of individual TLR, elucidation of their downstream signaling pathways, function of different adaptor proteins, activation of protein kinases and transcription factors that transcribe the genes for inflammatory molecules. TLRs not only sense microbial invasion but also can be activated by endogenous molecules as well as low molecular weight synthetic compounds. Given the role of innate immune machinery to provoke inflammation in host, TLRs signaling may be involved in many acute and chronic inflammatory processes in sterile and post-infection conditions such as, atherosclerosis, leprosy, inflammatory bowel syndrome (IBD), lung airway hyperactivity in allergic asthma, and in sepsis. By the same token, TLRs can also be associated with autoimmune diseases such as systemic lupus erythematosus (SLE) or other immune unresponsive diseases like cancer. In addition, synthetic organic compounds which enhance the function of TLRs can also be useful as potential adjutants to improve conventional vaccination strategy. Here we summarize the recent development on possible modulation of the TLR signaling pathway for therapeutic solution of multiple immune-related diseases. Keywords: toll like receptors, agonist-antagonist, inflammation, allergic asthma, cancer, atherosclerosis and vaccine
Bacterial lipopolysaccharide (LPS), one of the most potent inducers of inflammation, activates the transcription factor NF-κB to induce expression of both proinflammatory mediators and anti-microbial glycoproteins such as lipocalin 2 (Lcn2) and pentraxin 3 (PTX3) in macrophages. Glucocorticoids are known to inhibit LPS-induced expression of proinflammatory cytokines via glucocorticoid receptor (GR)-mediated transrepression of NF-κB, whereas their effect on induction of anti-microbial effectors has remained to be elucidated. Here we show that the synthetic glucocorticoid dexamethasone (Dex) strongly enhances LPS-induced transcription of Lcn2 and Ptx3, although Dex by itself fails to trigger their transcription. In macrophages deficient in IκBζ (an inducible coactivator of NF-κB), Lcn2 and Ptx3 are not activated by LPS either alone or in combination with Dex. Association of GR as well as Brg1 (a subunit of the chromatin remodelling Swi/Snf complex) with a functional glucocorticoid response element in Lcn2 requires both the costimulation with LPS and the presence of IκBζ. Although Ptx3 does not contain the element, LPS induces recruitment of Dex-liganded GR to NF-κB-binding sites in regulatory regions of Ptx3, an event that does not occur in IκBζ-deficient macrophages. Thus glucocorticoids likely regulate infection-induced inflammation by increasing anti-microbial effectors in an IκBζ-dependent manner, while repressing proinflammatory genes.
