Reduction in Human Epidermal Langerhans Cells with Age Is Associated with Decline in CXCL14-Mediated Recruitment of CD14+ Monocytes

Abstract

The skin provides the first line of physical and immunological defense against environmental insults. However, the age-related changes in the immune function of human skin are unclear. Here, we investigated the agerelated changes in epidermal Langerhans cells (LCs), which play a sentinel role in the initiation of the immune responses in the skin. We found a significant reduction in the number of epidermal LCs in sun-protected skin with age. Among the possible explanations for this reduction, the number of CD14 þ CD207 þ CCR6 þ dermal-resident monocytes that can differentiate into epidermal LCs was markedly reduced with age (P ¼ 0.0057). Among the chemokines that can recruit these cells into the skin, the expression of CXCL14 was significantly down-regulated in epidermal keratinocytes with age. In addition, we discovered that young skin recruited a significantly higher number of monocytic THP-1 cells compared with old skin ex vivo. This recruitment was blocked by CXCL14 neutralizing antibody and conversely promoted by CXCL14 treatment. Collectively, our findings indicate that decreased CXCL14-mediated recruitment of CD14 þ monocytes in human skin results in the reduction of epidermal LCs with age, and CXCL14 may provide a therapeutic target for the prevention of age-related reduction in LCs.

IL-34 Downregulation‒Associated M1/M2 Macrophage Imbalance Is Related to Inflammaging in Sun-Exposed Human Skin

“…Indeed, it has been reported that it is important to modify the pathways that initiate resolution processes, including efferocytosis, by M2-like macrophages to treat chronic inflammatory pathology ( Fullerton and Gilroy, 2016 ). Interestingly, IL-34 shows tissue-specific expression in the skin and is downregulated in sun-exposed skin of individuals in their age 60s, and a previous report indicated that the expression of IL-34 in sun-protected skin does not change with aging, suggesting that the IL-34 downregulation‒mediated increase in the M1-to-M2 ratio with aging may be a specific pathway in the skin, especially in sun-exposed areas ( Baghdadi et al., 2018 ; Carithers et al., 2015 ; Hasegawa et al., 2020 ). Therefore, aging-related downregulation of IL-34 in keratinocytes may explain the increase in the M1-to-M2 ratio and constitutes a possible mechanism underlying the accelerated inflammaging of sun-exposed skin.…”

Reduced Incidence of Necrotizing Enterocolitis due to the Anti-Inflammatory Effects of CXCL14 in Intestinal Tissue

“…CXCL14 (or BRAK or MIP-2 γ ), a member of the CXC family, is encoded by the chemokine (C-X-C Motif) ligand 14 genes located on human chromosome 5q31; previous researches demonstrate that the main functions of CXCL14 are immune regulation [ 19 , 20 ], anti-inflammatory [ 21 ], fibrosis [ 22 ], angiogenesis [ 23 ] and cancer progression [ 24 ]. More and more attention has been paid to research concerning the CXCL14 in acute immune including the chemotaxis and differentiation of immune cells [ 25 ], immunological surveillance [ 26 ].…”

Transcriptional profiling of macrophages in situ in metastatic melanoma reveals localization-dependent phenotypes and function

“…iCD3 + T cells showed higher expression of TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains) (p = 0.03), TMC4 (an ion channel), and PBX2 (a transcription factor potentially involved in T cell development) 33 , 34 ( Figure 3 D). sCD3 + T cells showed a higher expression of CXCL14, a chemoattractant for macrophages, immature DC, and natural killer (NK) cells 35 , 36 (p = 0.039; Figure 3 D) and of UTP14C (ribosome biogenesis) ( Figure 3 D). Interestingly, the exhaustion signature 37 was present in CD3 + T cells from both localizations ( Figure S9 ).…”