Dysregulation of the initial, innate immune response to bacterial infection may lead to septic shock and death. Toll-like receptors (TLRs) play a crucial role in this innate immune response, and yet the regulatory mechanisms controlling microbial-induced TLR triggering are still to be fully understood. We have therefore sought specific regulatory mechanisms that may modulate TLR signaling. In this study, we tested for the possible existence of a functionally active soluble form of TLR2. We demonstrated the existence of natural soluble forms of TLR2 (sTLR2), which we show to be capable of modulating cell activation. We found that blood monocytes released sTLR2 constitutively and that the kinetics of sTLR2 release increased upon cell activation. Analysis of cells expressing the human TLR2 cDNA or its c-myc-tagged version indicated that sTLR2 resulted from the posttranslational modification of the TLR2 protein in an intracellular compartment. Moreover, an intracellular pool of sTLR2 is maintained. sTLR2 was found naturally expressed in breast milk and plasma. Milk sTLR2 levels mirrored those of the TLR coreceptor soluble CD14. Depletion of sTLR2 from serum resulted in an increased cellular response to bacterial lipopeptide. Notably, serum sTLR2 was lower in tuberculosis patients. Coimmunoprecipitation experiments and computational molecular docking studies showed an interaction between sTLR2 and soluble CD14 in plasma and milk. These findings suggest the existence of a novel and specific innate immune mechanism regulating microbial-induced TLR triggering, and may lead to new therapeutics for the prevention and/or treatment of severe infectious diseases.

Ultra-hot giant exoplanets receive thousands of times Earth’s insolation 1 , 2 . Their high-temperature atmospheres (>2,000 K) are ideal laboratories for studying extreme planetary climates and chemistry 3 – 5 . Daysides are predicted to be cloud-free, dominated by atomic species 6 and substantially hotter than nightsides 5 , 7 , 8 . Atoms are expected to recombine into molecules over the nightside 9 , resulting in different day-night chemistry. While metallic elements and a large temperature contrast have been observed 10 – 14 , no chemical gradient has been measured across the surface of such an exoplanet. Different atmospheric chemistry between the day-to-night (“evening”) and night-to-day (“morning”) terminators could, however, be revealed as an asymmetric absorption signature during transit 4 , 7 , 15 . Here, we report the detection of an asymmetric atmospheric signature in the ultra-hot exoplanet WASP-76b. We spectrally and temporally resolve this signature thanks to the combination of high-dispersion spectroscopy with a large photon-collecting area. The absorption signal, attributed to neutral iron, is blueshifted by −11±0.7 km s -1 on the trailing limb, which can be explained by a combination of planetary rotation and wind blowing from the hot dayside 16 . In contrast, no signal arises from the nightside close to the morning terminator, showing that atomic iron is not absorbing starlight there. Iron must thus condense during its journey across the nightside.

Little is known about innate immunity to bacteria after birth in the hitherto sterile fetal intestine. Breast-feeding has long been associated with a lower incidence of gastrointestinal infections and inflammatory and allergic diseases. We found in human breast milk a 48-kD polypeptide, which we confirmed by mass spectrometry and sequencing to be a soluble form of the bacterial pattern recognition receptor CD14 (sCD14). Milk sCD14 (m-sCD14) concentrations were up to 20-fold higher than serum sCD14 from nonpregnant, pregnant, or lactating women. In contrast, lipopolysaccharide (LPS)-binding protein was at very low levels. Mammary epithelial cells produced 48-kD sCD14. m-sCD14 mediated activation by LPS and whole bacteria of CD14 negative cells, including intestinal epithelial cells, resulting in release of innate immune response molecules. m-sCD14 was undetectable in the infant formulas and commercial (cows') milk tested, although it was present in bovine colostrum. These findings indicate a sentinel role for sCD14 in human milk during bacterial colonization of the gut, and suggest that m-sCD14 may be involved in modulating local innate and adaptive immune responses, thus controlling homeostasis in the neonatal intestine.

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