Polymorphonuclear neutrophils (PMN) play a key role in host defenses against invading microorganisms but also potentiate inflammatory reactions in case of excessive or misdirected responses. Release of the alarmin high-mobility group box 1 (HMGB1) by cells that die at an inflammatory site may act as an alert signal for the immune system. We studied the effect of HMGB1 on human PMN migration, using whole-blood samples to avoid cell activation associated with isolation procedures. HMGB1 50–100 ng/ml reduced baseline PMN migration as well as formyl-methionyl-leucyl-phenylalanine- and IL-8-induced PMN chemotaxis. This inhibitory effect was mediated by the RAGE receptor. In contrast, a higher HMGB1 concentration (5,000 ng/ml) had a chemoattractant effect on PMN through IL-8 production. This effect required the engagement of Toll-like receptors 2 and 4 in addition to the RAGE receptor. The A box component of HMGB1, which antagonizes the endogenous protein, reduced chemotaxis and also strongly inhibited the enhancement of PMN migration observed with the highest HMGB1 concentration. In contrast, the B box, reported to be the active form of HMGB1, exerted a chemoattractant effect. These results strongly point to a key regulatory role of HMGB1 in PMN recruitment to inflammatory tissues. The A box component could potentially serve to inhibit inappropriate PMN recruitment during chronic inflammatory disorders associated with excessive HMGB1 release.

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Androgenetic alopecia is a common form of pattern hair loss, characterized by miniaturized hair follicles (HFs) at the front and parietal scalp, while hairs on the occipital scalp are preserved. Moreover, different body sites exhibit distinct types and patterns of HFs and understanding the molecular basis for this heterogeneity is important to design targeted treatment strategies. The Wnt signalling pathway and its Dickkopf (Dkk) inhibitors have been suggested to regulate HF type and patterning. We have previously shown that Dkk4 is specifically expressed in the epithelial placodes of HFs during mouse skin development. To elucidate the functions of Dkk4 in HF patterning, in this work, we used CRISPR/Cas9 to generate Dkk4-knockout mice. Dkk4 mutants showed disrupted HF patterning where the interplacodal distance was increased. Surprisingly, the lateral back skin of Dkk4 mutants was completely devoid of the first wave of HFs. In order to address the heterogeneity and regional differences in HF formation, we generated a Dkk4-EGFP knockin mouse line, which recapitulated the expression of Dkk4 in HF placodes. Our data revealed intra-and interplacodal differences in the expression of Dkk4-EGFP, suggesting that a WNT-DKK axis underlies the regional specificities in HF induction and patterning. Elucidating the molecular mechanisms of this heterogeneity will shed light on hair loss patterns such as in androgenetic alopecia.