Involvement of Toso in activation of monocytes, macrophages, and granulocytes

Abstract

Rapid activation of immune responses is necessary for antibacterial defense, but excessive immune activation can result in life-threatening septic shock. Understanding how these processes are balanced may provide novel therapeutic potential in treating inflammatory disease. Fc receptors are crucial for innate immune activation. However, the role of the putative Fc receptor for IgM, known as Toso/Faim3, has to this point been unclear. In this study, we generated Toso-deficient mice and used them to uncover a critical regulatory function of Toso in innate immune activation. Development of innate immune cells was intact in the absence of Toso, but Toso-deficient neutrophils exhibited more reactive oxygen species production and reduced phagocytosis of pathogens compared with controls. Cytokine production was also decreased in Toso −/− mice compared with WT animals, rendering them resistant to septic shock induced by lipopolysaccharide. However, Toso −/− mice also displayed limited cytokine production after infection with the bacterium Listeria monocytogenes that was correlated with elevated presence of Listeria throughout the body. Accordingly, Toso −/− mice succumbed to infections of L. monocytogenes , whereas WT mice successfully eliminated the infection. Taken together, our data reveal Toso to be a unique regulator of innate immune responses during bacterial infection and septic shock.

The Long Elusive IgM Fc Receptor, FcμR

“…The FcμR expression began at the early immature B cell stage in bone marrow and continued through to plasmablast stage of differentiation, accompanied by transient down-modulation during GC reactions 6 . Contrary to this, Lang et al recently reported that Ly6G + bone marrow granulocytes and Mφs expressed FcμR at extremely low density on their cell surface 57 . Strangely, Ly6G - bone marrow cells which should contain a significant number of FcμR-expressing B cells, were negative with their B68 mAb 57 .…”

“…Contrary to this, Lang et al recently reported that Ly6G + bone marrow granulocytes and Mφs expressed FcμR at extremely low density on their cell surface 57 . Strangely, Ly6G - bone marrow cells which should contain a significant number of FcμR-expressing B cells, were negative with their B68 mAb 57 . In this regard, we reexamined extensively and found that none of our mAbs reacted specifically with the cell surface of these phagocytes and that FcμR transcripts were clearly detectable in B-lineage cells but not in the double sorted Ly6G + granulocytes or in Rag1 -deficient splenocytes, which were devoid of B and T cells but contained abundant granulocytes and Mφs, even after 35 cycles of amplification 6, 58 .…”

“…Fcmr KO mice have been independently generated by two laboratories, our collaborator Hiroshi Ohno at RIKEN in Yokohama and Tak Mak at Ontario Cancer Institute in Toronto, and recently have been characterized by four different groups of investigators and there are clear differences in the reported phenotypes 6, 57, 59, 60 . Although the basis for these discrepancies requires further investigations, it might be due to different strategies for gene targeting [ i.e., deletion of exon 2 to 4 6, 59 versus exon 2 to 8 57, 60 and the absence 6, 59 versus presence of the Neo gene 57, 60 in the mouse genome] or to other differences in mouse ages, environments including intestinal flora or reagents used.…”

“…Although the basis for these discrepancies requires further investigations, it might be due to different strategies for gene targeting [ i.e., deletion of exon 2 to 4 6, 59 versus exon 2 to 8 57, 60 and the absence 6, 59 versus presence of the Neo gene 57, 60 in the mouse genome] or to other differences in mouse ages, environments including intestinal flora or reagents used. Nevertheless, the abnormal phenotypes commonly observed (in at least two laboratories) in Fcmr KO mice are: ( i ) increase in pre-immune serum IgM 6, 59 , ( ii ) alterations in B cell subpopulations 6, 59, 54 , ( iii ) dysregulation of humoral immune responses 6, 59, 54 , ( iv ) impairment of B cell proliferation upon ligation of BCR in vitro 59, 60 , and ( v ) predisposition to autoantibody production 6, 59, 54 .…”

Nomenclature of Toso, Fas Apoptosis Inhibitory Molecule 3, and IgM FcR

“…The Journal of Immunology, 2015, 194: 4055-4057. Two laboratories (Ohno and Mak) had generated Fcmr/ Toso-deficient mice, and from 2012 to 2015 four groups of investigators independently characterized their phenotypes (11)(12)(13)(14)(15)(16)(17)(18)(19). Clear differences in the reported phenotypes, in addition to the cellular distribution of FcmR/Toso, were evident but are not discussed in this article because they are not directly related to the topic of this meeting.…”