The innate immune system deploys a variety of pattern-recognition receptors (PRRs) which include Toll-like receptors (TLRs), RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors to detect the invasion of pathogens and initiate protective responses. The intercellular and intracellular orchestration of signals from different PRRs, their endogenous or microbial ligands and accessory molecules determine the stimulatory or inhibitory responses. Progressing over the last two decades, considerable research on the molecular mechanisms underlying host-pathogen interactions has led to a paradigm shift of our understanding of TLR signaling in the innate immune system. Given that a significant amount of evidence implicates TLRs in the pathogenesis of immune diseases and cancer, and their activation occurs early in the inflammatory cascade, they are attractive targets for novel therapeutic agents. In this review, we discuss the recent advances in TLR signaling cross talks and the mechanism of pathogen recognition with special emphasis on the role of TLRs in tumor immunity and TLR-targeted therapeutics.

Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF‐κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF‐κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1‐Associated Factor 60 (BAF60) proteins as well as IκB‐ζ, which forms a complex with the NF‐κB p50 subunit. These interactions are essential for Toll‐like receptor‐, RIG‐I‐, and Listeria‐mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB‐ζ recruitment to the Il6 promoter depend upon the presence of IκB‐ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB‐ζ–Akirin2–BAF60 complex physically links the NF‐κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB‐ζ, transcriptional coactivator for NF‐κB, the conserved nuclear protein Akirin2 stimulates pro‐inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection. Synopsis By recruiting SWI/SNF chromatin remodellers to NF‐κB, the conserved nuclear protein Akirin2 stimulates pro‐inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection. Akirin2 is critical for Toll‐like receptor‐ and RIG‐I‐like receptor‐induced cytokine production in mouse macrophages Akirin2 is critical for the responses to Listeria monocytogenes infection in living mice Akirin2 enables LPS‐induced chromatin remodelling in a SWI/SNF‐dependent manner The NF‐κBp50‐IκB‐ζ‐Akirin2 cascade is critical for the recruitment of Brg1, the SWI/SNF core catalytic subunit, to the Il6 promoter.

Polyubiquitination of proteins plays a critical role in the activation of immune cells. K63-linked polyubiquitin-binding proteins TGF-β–activated kinase 1 (TAK1)–binding protein (TAB)2 and TAB3 are implicated in NF-κB signaling via TAK1 activation. However, TAB2 alone is dispensable for NF-κB activation in embryonic fibroblasts, and the functional roles of TAB2 and TAB3 in immune cells has yet to be clarified. In this study, we demonstrate that TAB2 and TAB3 are essential for B cell activation leading to Ag-specific Ab responses, as well as B-1 and marginal zone B cell development. TAB2 and TAB3 are critical for the activation of MAPKs, especially ERK, but not NF-κB, in response to TLR and CD40 stimulation in B cells. Surprisingly, TAB2 and TAB3 are dispensable for TAK1 activation in B cells, indicating that TAB2 and TAB3 activate MAPKs via a pathway independent of TAK1. In contrast to B cells, macrophages lacking TAB2 and TAB3 did not show any defects in the cytokine production and the signaling pathway in response to TLR stimulation. Furthermore, TAB2 and TAB3 were dispensable for TNF-induced cytokine production in embryonic fibroblasts. Thus, TAB2- and TAB3-mediated K63-linked polyubiquitin recognition controls B cell activation via MAPKs, but not the TAK1/NF-κB axis.