Cathelicidin LL-37 Affects Surface and Intracellular Toll-Like Receptor Expression in Tissue Mast Cells

Abstract

Undoubtedly, mast cells take part in host defense against microorganisms as they are numerous at the portal of infection, they release many proinflammatory and antimicrobial mediators, and they express pattern recognition receptors, such as TLRs. These receptors play a key role in recognition and binding molecules associated with microorganisms and molecules associated with damage. Cathelicidins exhibit direct antimicrobial activities against a broad spectrum of microbes by perturbing their cell membranes. Accumulating evidence suggests a role for these molecules in supporting cell activation. We examined the impact of human cathelicidin LL-37 on tissue mast cell TLR expression and distribution. Depending on context, we show that LL-37 stimulation resulted in minor to major effects on TLR2, TLR3, TLR4, TLR5, TLR7, and TLR9 expression. Confocal microscopy analysis showed that, upon stimulation, TLRs may translocate from the cell interior to the surface and conversely. FPR2 and EGFR inhibitors reduced the increase in expression of selected receptors. We also established that LL-37 acts as a powerful inducer of CCL3 and ROS generation. These results showed that in response to LL-37, mast cells enhance the capability to detect invading pathogens by modulation of TLR expression in what may be involved FPR2 or EGFR molecules.

The RLR/NLR expression and pro-inflammatory activity of tissue mast cells are regulated by cathelicidin LL-37 and defensin hBD-2

“…LL-37 is known to influence TLR levels directly, enhancing TLR2, TLR4 and TLR9 expression on the surface of MCs, and TLR3, TLR5 and TLR7 in their interior 22 . These findings led us to investigate whether LL-37 and another HDP, i.e., defensin hBD-2, exert a similar effect on NLR and RLR expression.…”

“…These findings paved the way for research on the impact of HDPs on pattern recognition receptors (PRRs), which bind not only to pathogen-associated molecular patterns (PAMPs) but importantly, also to the endogenous molecules termed damage-associated molecular patterns (DAMPs) released from stressed or dying cells. We have been found that LL-37 affects Toll-like receptor (TLRs) expression, enhancing TLR2, TLR4, and TLR9 on the MC surface, and TLR3, TLR5, and TLR7 in the cell interior 22 . Previously, Yoshioka et al .…”

The Response of Tissue Mast Cells to TLR3 Ligand Poly(I:C) Treatment

“…To our knowledge, the exclusive study indicating TLR3 molecule, both intracellular and surface, in native mature murine MCs was suggested by Orinska et al [31]. Previously, we reported the mRNA and protein TLR3 expression in in vivo differentiated mature tissue MCs isolated from the rat peritoneal cavity [33]. In our research, by the use of western blot and flow cytometry techniques, we have confirmed that fully mature native rPMCs express TLR3 protein, wherein by the second method, we additionally confirmed the presence of TLR3 molecule both intracellularly and on the cell surface.…”

“…It might be speculated that those cells are capable of responding to virus-derived components and thereby involved in antiviral host defense on the one hand and pathomechanism of viral diseases on the other. According to some reports, MCs express PRRs responsible for the recognition of virusderived PAMPs, mainly intracellular TLR3, TLR7, TLR9, and RIG-I [27][28][29][30][31][32][33][34]. The presence of the TLR3 transcript and protein is described and demonstrated both in MC lines and in various MCs differentiated in vivo.…”

An overview of mast cell pattern recognition receptors

“…Data indicate that MCs express TLR1–10 and there is no information confirming the presence of TLR11–13. Additionally, our recent data revealed that nearly every TLR might be expressed either in MC plasma membrane as well as inside the cell [ 38 , 39 ]. More detailed data concerning this issue are already described in other reviews [ 30 , 31 ].…”