Age-related changes in expression and function of Toll-like receptors in human skin

Abstract

Toll-like receptors (TLRs) initiate innate immune responses and direct subsequent adaptive immunity. They play a major role in cutaneous host defense against micro-organisms and in the pathophysiology of several inflammatory skin diseases. To understand the role of TLRs in the acquisition of immunological competence, we conducted a comprehensive study to evaluate TLR expression and function in the developing human skin before and after birth and compared it with adults. We found that prenatal skin already expresses the same spectrum of TLRs as adult skin. Strikingly, many TLRs were significantly higher expressed in prenatal (TLRs 1-5) and infant and child (TLRs 1 and 3) skin than in adult skin. Surprisingly, neither dendritic cell precursors in prenatal skin nor epidermal Langerhans cells and dermal dendritic cells in adult skin expressed TLRs 3 and 6, whereas the staining pattern and intensity of both TLRs in fetal basal keratinocytes was almost comparable to those of adults. Stimulation of primary human keratinocytes from fetal, neonatal and adult donors with selected TLR agonists revealed that the synthetic TLR3 ligand poly (I:C) specifically, mimicking viral double-stranded RNA, induced a significantly enhanced secretion of CXCL8/IL8, CXCL10/IP-10 and TNFα in fetal and neonatal keratinocytes compared with adult keratinocytes. This study demonstrates quantitative age-specific modifications in TLR expression and innate skin immune reactivity in response to TLR activation. Thus, antiviral innate immunity already in prenatal skin may contribute to protect the developing human body from viral infections in utero in a scenario where the adaptive immune system is not yet fully functional.

Macrophage- and Neutrophil-Derived TNF-α Instructs Skin Langerhans Cells To Prime Antiviral Immune Responses

“…Flacher et al reported that LCs were activated by poly(I:C) (26) although this was not confirmed in our study or in previous works (43). Differences in TLR-L doses and in the origin and purity of the cell populations used may account for these discrepancies.…”

“…Differences in TLR-L doses and in the origin and purity of the cell populations used may account for these discrepancies. Keratinocytes and inflammatory cells, such as macrophages which express TLR3 to significant levels, may play a predominant role in the adjuvant effect observed with poly(I:C) (43). Further evidence for the predominant role of macrophages is provided by the demonstration that poly(I:C) can activate macrophages in different ways, including TLR3-independent Mac-1 antigen-binding (44).…”

Epicutaneous administration of the pattern recognition receptor agonist polyinosinic‐polycytidylic acid activates the MDA5/MAVS pathway in Langerhans cells

“…In line with reported qPCR results (19) and our previous immunostaining (34), we found bright TLR3 expression in basal KCs in cryosections and moderate TLR3 levels in primary KCs but not in CD207 + LCs ( Fig. 3 A and Supplemental Fig.…”

The Skin as a Route of Allergen Exposure: Part I. Immune Components and Mechanisms

“…DC expression of Toll-like receptors (TLRs) is another critical determinant of downstream T cell responses. Patterns of surface and endosomal TLR expression on human skin DCs vary by subset and activation status [23, 24] and differ in adult compared to neonatal skin [35]. The ontogeny of functional skin DC subsets in relation to allergy remains enigmatic.…”