TLR3-, TLR7-, and TLR9-Mediated Production of Proinflammatory Cytokines and Chemokines from Murine Connective Tissue Type Skin-Derived Mast Cells but Not from Bone Marrow-Derived Mast Cells

Abstract

Recent studies have revealed that murine bone marrow-derived cultured mast cells (BMMC), which are phenotypically immature mast cells, express functional TLR2 and TLR4 that recognize distinct pathogen-associated molecules. However, it remains relatively uncertain whether mast cells express other TLR. We recently established a method to obtain large numbers of murine fetal skin-derived cultured mast cells (FSMC); these cells exhibit important features of connective tissue type mast cells. Working with FSMC and BMMC, the TLR mRNA expression profiles were compared between both cell types. Although TLR2 and TLR4 mRNA were detected in both cells at comparable levels, TLR3, TLR7, and TLR9 mRNA were expressed by FSMC at higher levels than by BMMC, suggesting distinct TLR expression profiles among different mast cell populations. With respect to their functional aspects, FSMC, but not BMMC, dose dependently produced proinflammatory cytokines (TNF-α and IL-6) and chemokines (RANTES, MIP-1α, and MIP-2) in response to poly(I:C), R-848, and CpG oligodeoxynucleotide, which are TLR3, TLR7, and TLR9 activators, respectively. Interestingly, these TLR activators failed to induce degranulation and IL-13 production by both mast cells, although peptidoglycan and LPS (TLR2 and TLR4 activators, respectively) induced IL-13 production by both cells. Mast cells, thus, may have potential to recruit other immune cells to the infected sites by responding to various bacterial and viral components through TLR signaling pathways, presumably being involved in initiating innate immunity and subsequently linking innate and acquired immune responses.

LocalSalmonellaimmunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor

“…[2][3][4][5] An alternative approach, irrespective of the immunization route, is to enhance T-cell attraction to the tumor site through the local application of selected chemokines 6 or Toll-like receptor (TLR) agonists that are able to modify the expression of selectins, integrins, chemokines, and chemokine receptors. 7,8 Along this line, we recently reported that intravaginal (IVAG) administration of CpG (a TLR-9 agonist) resulted in the accumulation of CD8 T cells co-expressing CCR5 and CXCR3 chemokine receptors and E-selectin ligands (ESL), most probably through CpG-induced expression of CCL5, CXCL9, CXCL10, CXCL11, and/or E-selectin 9 . Most importantly, in a murine model of cervical cancer, this strategy resulted in more efficient genital tumor regression than vaccination alone.…”

Mast cells as rapid innate sensors of cytomegalovirus by TLR3/TRIF signaling-dependent and -independent mechanisms

“…8 The receptor repertoire includes numerous pattern recognition receptors (PRRs), which encompass most Toll-like receptors (TLRs), including TLR3 and TLR9. [9][10][11] In addition, MCs are reported to express complement receptors, G proteincoupled receptors, and CD48. This equipment enables MCs to recognize a wide array of exogenous ligands, pathogenassociated molecular patterns and endogenous ligands, all of which trigger danger signals in the host.…”

Blockade of Lyn kinase upregulates both canonical and non-canonical TLR-3 pathways in THP-1 monocytes exposed to human cytomegalovirus

“…TLRs serve as sensors against pathogens that invade the host by recognizing pathogen-associated molecular patterns (Matsushima et al, 2004). Each TLR has been identified to recognize a distinct ligand, supported and confirmed by previous observation of TLR-knockout mice and specific gene modifications.…”

“…During HCMV infection, monocytes and their derivative cells, which represent the first line of defense, are thought to participate in innate immune response by restricting viral dissemination. Experimental studies indicate that recognition or binding of HCMV particles, which can take place either on the cell surface (Hampton et al, 1991;Peiser et al, 2002;Abate et al, 2004;DeWitte-Orr et al, 2010) or within intracellular endosome (Jiang et al, 2004;Matsushima et al, 2004;Jiang et al, 2009), is an early and potent regulatory signal for the activation of pro-inflammatory cytokines. Monocyte-derived cytokines are essential in triggering T-cell response.…”

“…Each TLR has been identified to recognize a distinct ligand, supported and confirmed by previous observation of TLR-knockout mice and specific gene modifications. For example, TLR-3 and TLR-9 recognize viral dsRNA and unmethylated consensus DNA sequences, including the CpG motif in bacteria and viruses, respectively (Matsushima et al, 2004). All TLRs mediate signaling through their cytoplasmic TIR domains linked to adaptor proteins, such as MYD-88 and TRIF, which induce the activation of NF-κB and IRF3, respectively.…”