TLR2 Regulates Mast Cell IL-6 and IL-13 Production During Listeria monocytogenes Infection

Abstract

Listeria monocytogenes (L.m) is efficiently controlled by several cells of the innate immunity, including the Mast Cell (MC). MC is activated by L.m inducing its degranulation, cytokine production and microbicidal mechanisms. TLR2 is required for the optimal control of L.m infection by different cells of the immune system. However, little is known about the MC receptors involved in recognizing this bacterium and whether these interactions mediate MC activation. In this study, we analyzed whether TLR2 is involved in mediating different MC activation responses during L.m infection. We found that despite MC were infected with L.m, they were able to clear the bacterial load. In addition, MC degranulated and produced ROS, TNF-α, IL-1β, IL-6, IL-13 and MCP-1 in response to bacterial infection. Interestingly, L.m induced the activation of signaling proteins: ERK, p38 and NF-κB. When TLR2 was blocked, L.m endocytosis, bactericidal activity, ROS production and mast cell degranulation were not affected. Interestingly, only IL-6 and IL-13 production were affected when TLR2 was inhibited in response to L.m infection. Furthermore, p38 activation depended on TLR2, but not ERK or NF-κB activation. These results indicate that TLR2 mediates only some MC activation pathways during L.m infection, mainly those related to IL-6 and IL-13 production.

Valproic acid restricts mast cell activation by Listeria monocytogenes

“…In this regard, it is known that the mitogen-activated protein kinase (MAPK) and NF-κB pathways are induced in macrophages infected with L.m, and that their activation is associated with cytokine synthesis 32 – 34 . In addition, recent work has demonstrated that L.m activates these two signaling pathways in MC 14 .

Figure 4 Valproic acid decreases calcium mobilization and phosphorylation of signaling proteins in Listeria monocytogenes -activated mast cells.

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“…Toll-Like Receptor (TLR2) plays an important role in innate immune defense against L.m and the early secretion of pro-inflammatory cytokines 28 . The importance of MC TLR2 during infection with Francisella tularensis 29 and L.m 14 has been well established. Therefore, we evaluated whether VPA affected TLR2 expression.…”

“…L.m also activates MC in a TLR2-independent manner through Listeriolysin O (LLO) toxin which activates MC in a cholesterol dependent pathway 14 , 30 . Therefore, we evaluated whether VPA could affect LLO-induced degranulation and cytokine secretion by MC.…”

“…In vitro and in vivo models of listeriosis have shown that MC play a critical role controlling L.m infection by degranulating and releasing pro-inflammatory cytokines which induce early recruitment of neutrophils to the site of infection 9 , 12 . In addition, MC restrict L.m growth through endocytosis, reactive oxygen species (ROS) production 13 , 14 , and by the release of extracellular traps 15 . Since the mechanisms of MC activation in response to L.m are well known 13 – 16 , it is possible to evaluate whether they are susceptible to modulation by different drugs.…”

Involvement of CCN1 Protein and TLR2/4 Signaling Pathways in Intestinal Epithelial Cells Response to Listeria monocytogenes

“…This phenomenon was consistent with the previous report of L. monocytogenes infection [ 36 , 37 ]. In addition, the ratio of P-p38/p38 in protein level and the p38 in mRNA level was also up-regulated in mice and intestinal organoids, which indicates that the downstream MAPK pathway had been activated to induce inflammation after L. monocytogenes infection [ 38 ].…”