Mast cells are crucial for early inflammation, migration of Langerhans cells, and CTL responses following topical application of TLR7 ligand in mice

Abstract

Until recently, IgE-activated mast cells have been regarded merely as effector cells of adaptive immune responses, involved in allergic reactions and mucosal immunity to parasites. Herein, we report that murine dermal mast cells, activated by local administration of a cream containing the synthetic TLR7 ligand imiquimod, are essential to initiate an early inflammatory reaction. The mast-cell-derived cytokines TNF-␣ and IL-1␤ play an important role in this process. Furthermore, TLR7-activated mast cells are also able to promote the emigration of Langerhans cells, which partly depends on the expression of mast-cell-derived IL-1␤. We have previously shown that TLR7 ligation enhances transcutaneous immunization evoked by topical application of vaccine antigens to the skin, a procedure that directly targets skin-resident antigen-presenting cells.Consequently, we now demonstrate here that the capacity to mount a peptidespecific cytotoxic T-lymphocyte response following transcutaneous immunization using imiquimod as adjuvant is severely impaired in mast-cell-deficient mice. IntroductionIgE-dependent reactions including dysregulated allergic responses to environmental antigens and mucosal immunity to some extracellular parasites were believed to be the hallmarks of mast-cell immunology for several decades.We know by now that mast cells, predominantly localized at the interface between host and environment (ie, skin and mucosal surfaces), are in addition able to perceive a variety of allergens and invading pathogens. Based on 2 groundbreaking publications using murine models of acute bacterial infection, mast cells were found to be critical effectors of innate immunity. In these studies, mastcell-deficient mice were highly susceptible to induced septic peritonitis 1 and Klebsiella pneumoniae instillation. 2 In these settings, the unique ability of mast cells to secrete preformed TNF-␣ within minutes following IgE-independent stimulation enables the host to mount an early and protective neutrophil response to bacterial challenge. Evidence further accumulates that mast cells are implicated in host defense against a still increasing range of clinically relevant bacterial infections. [3][4][5] Furthermore, mast cells are also thought to participate in response to viruses, but this is less understood and deserves further research. 5,6 With respect to IgEindependent activation, both rodent and human mast cells were found to express a variety of Toll-like receptors, some of which are expressed only on certain mast cell subsets. [5][6][7] However, several murine in vivo models clearly showed the importance of TLRmediated mast cell activation, for example, for the clearance of enterobacterial infection by triggering TLR4 8 and for the recruitment of CD8 ϩ T cells into the peritoneal cavity following ligation of TLR3 with poly(I:C), which mimics viral dsRNA. 9 It is also increasingly being appreciated that mast cells are able to finely control the magnitude of the secretory response following activation. 10 Thus, IgE-independent ...

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“…Administration of poly(I:C) or R848 in addition to allergen have both been described to induce allergen-specific CD8 + T cells and Th1 cytokine production when applied via the skin (41,42). However, in the current model only administration of TLR3 ligand into the lung resulted in an inflammatory response with increased numbers of lymphocytes and eosinophils in the airways and increased expression of cytokines and chemokines.…”

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

“…Furthermore, dermal mast cells were shown to be essential in the imiquimod-induced immune response. Both early cutaneous inflammation and migration of Langerhans cells were promoted by TLR7-activated mast cells, with mast cell-derived TNF-␣ and IL-1 as the essential mediators [55].…”

Circadian gene clock regulates psoriasis-like skin inflammation in mice

“…Mast cells have a regulatory role in the development of IMQinduced dermatitis in mice-in particular, in the initiation phase of dermatitis-via regulation of tumor necrosis factor-α and IL-1β (Heib et al, 2007). In addition, we have previously shown that Clock mutation affects IgE-mediated mast cell responses (Nakamura et al, 2011(Nakamura et al, , 2014.…”