VSFS revealed that Zn2+ and Ca2+ were bound to the phosphate and carboxylate moieties on PS via contact ion pairing, dehydrating the lipid headgroup, whereas Mg2+ and Cu(2+ )were bound without perturbing the hydration of these functional groups. The interactions of divalent metal cations with PS lipids were further investigated by a combination of vibrational sum frequency spectroscopy (VSFS) and surface pressure-area isotherm measurements. Moreover, Ca2+ can induce some blebbing at mM concentrations but not nearly as effectively as Zn2+. Bleb formation is ion specific, inducible by exposing the bilayer to mu M concentrations of Zn2+ but not Mg2+, Cu2+, Co-,(2+) or Mn2+. Measurements using atomic force microscopy (AFM) reveal that these spots represent three-dimensional unilamellar blebs. This reordering is manifest through bright spots of high fluorescence intensity that can be observed when the bilayer contains a dye-labeled lipid. Significantly, Zn2+ binding to SLBs containing more than 10 mol % PS induces extensive reordering of the bilayer. Herein, we show that Zn2+ binds to phosphatidylserine (PS) lipids in supported lipid bilayers (SLBs), forming a PS-Zn2+ complex with an equilibrium dissociation constant of similar to 100 mu M. A possible critical role of aryl hydrocarbon receptor (AhR) in regulating the B cell function is discussed, as we find that AhR is among the preferentially expressed transcription factors in Tim-1(+) B cells and regulates their TIGIT and IL-10 expression.
Our findings suggest that Tim-1(+) B cells are essential for maintaining self-tolerance and restraining tissue inflammation, and that Tim-1 signaling-dependent TIGIT expression on B cells is essential for maintaining CNS-specific tolerance. Mice with B cell-specific TIGIT deletion develop spontaneous paralysis with CNS inflammation, but with limited inflammation in other organs. Transcriptomic analysis demonstrates that besides IL-10, Tim-1(+) B cells also differentially express a number of co-inhibitory checkpoint receptors including TIGIT. Here we show that mice with B cell-specific Tim-1 deletion develop tissue inflammation in multiple organs including spontaneous paralysis with inflammation in the central nervous system (CNS). Tim-1, a phosphatidylserine receptor expressed on B cells, induces interleukin 10 (IL-10) production by sensing apoptotic cells.
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