Gut Dysbiosis Promotes M2 Macrophage Polarization and Allergic Airway Inflammation via Fungi-Induced PGE2

SummaryAlthough imbalances in gut microbiota composition, or “dysbiosis,” are associated with many diseases, the effects of gut dysbiosis on host systemic physiology are less well characterized. We report that gut dysbiosis induced by antibiotic (Abx) treatment promotes allergic airway inflammation by shifting macrophage polarization in the lung toward the alternatively activated M2 phenotype. Adoptive transfer of alveolar macrophages derived from Abx-treated mice was sufficient to increase allergic airway inflammation. Abx treatment resulted in the overgrowth of a commensal fungal Candida species in the gut and increased plasma concentrations of prostaglandin E2 (PGE2), which induced M2 macrophage polarization in the lung. Suppression of PGE2 synthesis by the cyclooxygenase inhibitors aspirin and celecoxib suppressed M2 macrophage polarization and decreased allergic airway inflammatory cell infiltration in Abx-treated mice. Thus, Abx treatment can cause overgrowth of particular fungal species in the gut and promote M2 macrophage activation at distant sites to influence systemic responses including allergic inflammation

The immunoreceptor adapter protein DAP12 suppresses B lymphocyte–driven adaptive immune responses

Human and mouse B cells lacking functional DAP12 are hyperresponsive, and DAP12 works with MAIR-II (CD300d) to negatively regulate B cell activity

Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adapters DAP12 and FcR gamma chain on peritoneal macrophages

Certain activating immune receptors expressed on myeloid cells noncovalently associate with either DAP12 or Fc epsilon RI gamma (FcR gamma chain), the ITAM-bearing transmembrane adapter proteins. An activating receptor, myeloid-associated Ig-like receptor (MAIR) II, is expressed on a subset of B cells and macrophages in the spleen and peritoneal cavity of mice and associates with DAP12 in these cells. However, we demonstrate here that cross-linking MAIR-II with mAb induced secretion of a significant amount of the inflammatory cytokines TNF-alpha and IL-6 from DAP12(-/-) as well as wild-type (WT) peritoneal macrophages. We show that MAIR-II associates with not only DAP12 but also FcR gamma chain homodimers in peritoneal macrophages. LPS enhanced the FcR gamma chain expression and FcR gamma chain-dependent cell surface expression of MAIR-II and had additive effects on MAIR-II-mediated inflammatory cytokine secretion from peritoneal macrophages. The lysine residue in the transmembrane region of MAIR-II was involved in the association with FcR-y chain as well as DAP12. Our findings present the first case of an activating receptor that uses either DAP12 or FcRC gamma chain as a signaling adapter. The FcR-y chain may provide cooperation with and/or compensation for DAP12 in MAIR-II-mediated inflammatory responses by peritoneal macrophages

Solutions to Solar Neutrino Anomaly

We present an updated analysis of astrophysical solutions, two-flavor MSW solutions, and vacuum oscillation solutions to the solar neutrino anomaly. The recent results of each of the five solar neutrino experiments are incorporated, including both the zenith angle (day-night) and spectral information from the Kamiokande experiment, and the preliminary Super-Kamiokande results. New theoretical developments include the use of the most recent Bahcall-Pinsonneault flux predictions (and uncertainties) and density and production profiles, the radiative corrections to the neutrino-electron scattering cross section, and new constraints on the Ga absorption cross section inferred from the gallium source experiments. From a model independent analysis, arbitrary astrophysical solutions are excluded at more that 98% C.L. even if one ignores any one of the three classes of experiment, relaxes the luminosity constraint, or allows more suppression of the 7Be than 8B flux. The data is well described by large and small mixing angle two-flavor MSW conversions, MSW conversions into a sterile neutrino with small mixing, or vacuum oscillations. We also present MSW fits for nonstandard solar models parameterized by an arbitrary solar core temperature or arbitrary 8B flux.Comment: 36p including 21 postscript figures, uses REVTEX 3.1 and epsf.sty, entire ps file and html file with embedded figures available at http://www.sns.ias.edu/~hata/papers/anomaly

Model Independent Determination of the Solar Neutrino Spectrum with and without MSW

Besides the opportunity for discovering new neutrino physics, solar neutrino measurements provide a sensitive probe of the solar interior, and thus a rigorous test of solar model predictions. We present model independent determinations of the neutrino spectrum by using relevant flux components as free parameters subject only to the luminosity constraint. (1) Without the Mikheyev-Smirnov-Wolfenstein (MSW) effect, the best fit for the combined data is poor. Furthermore, the data indicate a severe suppression of the $^7$Be flux relative to the $^8$B, contradicting both standard and nonstandard solar models in general; the $pp$ flux takes its maximum value allowed by the luminosity constraint. This pathology consistently appears even if we ignore any one of the three data. (2) In the presence of the two-flavor MSW effect, the current constraint on the initial $^8$B flux is weak, but consistent with the SSM and sufficient to exclude nonstandard models with small $^8$B fluxes. No meaningful constraint is obtained for the other fluxes. In the future, even allowing MSW, the $^8$B and $^7$Be fluxes can be determined at the $\pm$(15 -- 20)\% level, making competing solar models distinguishable. We emphasize that the neutral current sensitivity for $^7$Be neutrinos in BOREXINO, HELLAZ, and HERON is essential for determining the initial fluxes. The constraints on the MSW parameters in the model independent analysis are also discussed.Comment: Revtex 3.0, 61 pages including 23 figures, uuencoded ps file attached. Easy way: compressed ps file of entire paper in landscape format available by anonymous ftp://upenn5.hep.upenn.edu/pub/hata/papers/model_ind.ps.