The alarmin Mrp8/14 as regulator of the adaptive immune response during allergic contact dermatitis

Abstract

Mrp8 and Mrp14 are endogenous alarmins amplifying inflammation via Toll‐like receptor‐4 (TLR‐4) activation. Due to their pro‐inflammatory properties, alarmins are supposed to enhance adaptive immunity via activation of dendritic cells (DCs). In contrast, analysing a model of allergic contact dermatitis (ACD) we observed a more severe disease outcome in Mrp8/14‐deficient compared to wild‐type mice. This unexpected phenotype was associated with an enhanced T‐cell response due to an accelerated maturation of DCs in Mrp8/14‐deficient mice. Accordingly, Mrp8, the active component of the heterocomplex, inhibits early DC maturation and antigen presentation in a TLR‐4‐dependent manner. Transfer of DCs purified from the local lymph nodes of sensitized Mrp8/14‐deficient to wild‐type mice determined the outcome of ACD. Our results link a pro‐inflammatory role of the endogenous TLR‐4 ligand Mrp8/14 to a regulatory function in adaptive immunity, which shows some similarities with the ‘hygiene hypothesis’ regarding continuous TLR‐4 stimulation and decreased risk of allergy.

Myeloid-related protein-14 deficiency promotes inflammation in staphylococcal pneumonia

“…This pro-inflammatory phenotype of mrp14 −/− mice is unlikely explained by differences in bacterial loads, considering that many dissimilarities were already present at 6 h after infection (when all bacterial counts were similar) and considering the only very modest variance in lung bacterial loads at 24 h. It is also not explained by different baseline cytokine and chemokine levels, as these are similar in BALF from naive wildtype and mrp14 −/− mice [42]. Recent studies demonstrated that mrp14 −/− mice have an enhanced maturation state of dendritic cells [43,44], and that these matured dendritic cells release more cytokines [44]. Notably, dendritic cells contribute to cytokine production during S. aureus pneumonia [45].…”

Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity

“…ICD was induced in Balb/c mice by the local application of croton oil towards the ear skin13. 18 F-FDG-PET, as a clinically established imaging technique to assess inflammatory activity14, was used to visualize elevated glucose metabolism in areas of inflammation during ICD.…”

The hand eczema proteome: imbalance of epidermal barrier proteins

“…New findings suggest that, beyond their antimicrobial activity, S100A8/A9 serve as an internal danger signal of activated keratinocytes, as both proteins are induced by tapestripping . Additionally, S100A8/A9 are also released during the sensitization phase of ACD …”