Cell fusion involving progenitor cells is a newly recognized phenomenon thought to contribute to tissue differentiation. The molecular mechanisms governing cell fusion are unknown. P-glycoprotein and related ATP-binding cassette transporters are expressed by progenitor cells, but their physiological role in these cell types has not been defined. Here, we have cloned ABCB5, a rhodamine efflux transporter and novel member of the human P-glycoprotein family, which marks CD133-expressing progenitor cells among human epidermal melanocytes and determines as a regulator of membrane potential the propensity of this subpopulation to undergo cell fusion. Our findings show that polyploid ABCB5 ؉ cells are generated by cell fusion and that this process is specifically enhanced by ABCB5 Pglycoprotein blockade. Remarkably, multinucleated cell hybrids gave rise to mononucleated progeny, demonstrating that fusion contributes to culture growth and differentiation. Thus, our findings define a molecular mechanism for cell fusion involving progenitor cells and show that fusion and resultant growth and differentiation are not merely spontaneous events, but phenomena regulated by ABCB5 P-glycoprotein.Several recent reports have demonstrated that co-culture of pluripotent embryonic or mesenchymal stem cells with lineagecommitted cell types can give rise to cell hybrids as a result of cell fusion, and it has been shown that such cell hybrids can generate differentiated progeny in vitro and in vivo (1-5). These findings raise the possibility that cell fusion may represent a physiological mechanism by which endogenous progenitor cells participate in tissue plasticity and renewal. A cellular molecular marker identifying progenitor cells participating in cell fusion or associated with the regulation of cell fusion has as of yet not been identified, however. P-glycoproteins (P-gp) 1 and related members of the ABC superfamily of active transporters mediate multidrug resistance in mammalian cancers (6 -13) and serve physiologic transport (14 -21), differentiation (22, 23), and survival (24, 25) functions in nonmalignant cell types. Two known members of the ABC superfamily of transporters, ABCB1 (MDR1) P-gp and the ABCG2 (Bcrp1) transporter, are also expressed at high levels on stem and progenitor cell populations (26, 27), and the efflux capacity for the fluorescent dyes rhodamine-123 (28 -30) and Hoechst 33342 (31-34) mediated by these or related ABC transporters has been utilized for the isolation of such cell subsets. A physiologic role of ABC transporters in such progenitor cells has, however, not been defined. A recent study investigated a possible role of ABCB1 P-gp as a determinant of membrane fluidity and membrane potential, but ABCB1 P-gp was found not responsible for the plasma membrane hyperpolarization observed in multidrug resistant cells (35). Here we have cloned and characterized a novel, third member of the human P-gp family encoded on chromosome 7p21-15.3, designated ABCB5 (ATP-binding cassette, subfamily B (MDR/TAP), member ...
Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.
Gut commensal bacteria play important roles in the development and homeostasis of intestinal immunity. However, the role of gut commensals in intestinal ischemia/reperfusion (I/R) injury is unclear. To determine the roles of gut commensal bacteria in intestinal IR injury, we depleted gut microbiota with a broad-spectrum antibiotic cocktail and performed mesenteric I/R (M I/R). First, we confirmed that antibiotic treatment completely depleted gut commensal bacteria and diminished the size of secondary lymphoid tissues such as the Peyer's patches. We next found that antibiotic treatment attenuated intestinal injury following M I/R. Depletion of gut commensal bacteria reduced the expression of Toll-like receptor (TLR)2 and TLR4 in the intestine. Both are well-known receptors for gram-positive and -negative bacteria. Decreased expression of TLR2 and TLR4 led to the reduction of inflammatory mediators, such as TNF, IL-6, and cyclooxygenase-2. Intestinal I/R injury is initiated when natural antibodies recognize neo-antigens that are revealed on ischemic cells and activate the complement pathway. Thus we evaluated complement and immunoglobulin (Ig) deposition in the damaged intestine and found that antibiotic treatment decreased the deposition of both C3 and IgM. Interestingly, we also found that the deposition of IgA also increased in the intestine following M I/R compared with control mice and that antibiotic treatment decreased the deposition of IgA in the damaged intestine. These results suggest that depletion of gut commensal bacteria decreases B cells, Igs, and TLR expression in the intestine, inhibits complement activation, and attenuates intestinal inflammation and injury following M I/R.
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