Deposition of antibody-antigen immune complexes (IC) in tissues underlies the pathogenesis of a range of human autoimmune diseases from glomerulonephritis, SLE and arthritis, to transplantation rejection. Infiltrating leukocytes are the cause of inflammatory tissue damage. The primary objective of this competing renewal remains an in depth study of the mechanisms of IC mediated neutrophil recruitment and injury. Receptors for IgG, collectively known as Fc(Rs, mediate the interaction of antibodies with effector cells. In the current grant period, we provide several lines of evidence that the low affinity activating neutrophil Fc(Rs in mice, which preferentially complex with IgG-ICs, directly mediate neutrophil accumulation. Neutrophil Fc(Rs and the leukocyte specific CD18 integrins cooperated to promote IC induced neutrophil slow rolling, adhesion and transmigration, and TNF priming of neutrophils enhanced these processes. There are notable structural differences between neutrophil human and mouse low affinity activating Fc(Rs. Mice express Fc(RIII and Fc(RIV which complex with the common (-chain to signal while human neutrophils express Fc(RIIA with the ITAM signaling and ligand binding domain in a single polypeptide chain, and a unique GPI-linked Fc(RIIIB. To examine the physiological functions, and the relative roles of the human neutrophil Fc(Rs in vivo, we expressed human Fc(RIIIB and Fc(RIIA selectively in neutrophils of mice lacking the common (-chain ((-/-) and thus endogenous activating FcRs. (-/- mice failed to develop anti-glomerular basement membrane induced progressive glomerulonephritis and soluble IC induced Reverse Passive Arthus reaction as expected. In contrast, mice expressing hFc(RIIA on neutrophils displayed significant tissue injury. Moreover, mice expressing either hFc(RIIIB or hFc(RIIA exhibited significant tissue neutrophil accumulation in both models. Using intravital microscopy, we demonstrate that neutrophil Fc(RIIA and Fc(RIIIB play specialized context-dependent roles in IC-mediated neutrophil slow rolling, adhesion and transmigration. From these, and related observations, we hypothesize that Fc(RIIA and Fc(RIIIB serve distinct nonredundant functions in response to ICs, which are differentially regulated. We propose that 1) Fc(RIIIB tethering to ICs, supported by CD18 integrins serves a homeostatic role in clearing intravascular ICs, while 2) Fc(RIIA mediated recruitment and associated injury is regulated by cytokines, resident mast cells and macrophages, and requires its ITAM motif. In this proposal we will rigorously test these hypothesis using our humanized Fc(R transgenics, mouse lines deficient in mast cells or macrophages, and cell reconstitution approaches coupled with well-characterized in vivo models of IC induced inflammation and intravital microscopy. We anticipate that the new information provided by this proposal will increase our understanding of mechanisms of IC-induced neutrophil recruitment and activation and provide therapeutic targets for antibody-mediated inflammation relevant to human disorders.
The objective of this proposal is to understand the role of human neutrophil Fc(Rs, receptors for IgG, in autoimmune diseases, which afflict 5-8% of the population. In mice, Fc(Rs have emerged as critical players in IC induced injury of the lung, skin and joints. However, the relevance of this to human inflammation remains unclear, as there are significant structural differences between activating Fc(Rs in mice and humans. We have generated mice expressing the two uniquely human activating neutrophil Fc(Rs, Fc(RIIA and Fc(RIIIB selectively in neutrophils and shown a predominant role for these human receptors in the initiation of immune complex-mediated diseases. Here we will further determine the physiological role of these receptors in neutrophil recruitment and injury in vivo. We anticipate that this will lead to the identification of therapeutic strategies that target tissue injury in inflammatory and autoimmune disorders relevant to human disease.
|Nishi, Hiroshi; Furuhashi, Kazuhiro; Cullere, Xavier et al. (2017) Neutrophil Fc?RIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases. J Clin Invest 127:3810-3826|
|Ernandez, Thomas; Mayadas, Tanya Norton (2016) The Changing Landscape of Renal Inflammation. Trends Mol Med 22:151-63|
|Rosetti, Florencia; Mayadas, Tanya N (2016) The many faces of Mac-1 in autoimmune disease. Immunol Rev 269:175-93|
|Rosetti, Florencia; Chen, Yunfeng; Sen, Mehmet et al. (2015) A Lupus-Associated Mac-1 Variant Has Defects in Integrin Allostery and Interaction with Ligands under Force. Cell Rep :|
|Mayadas, Tanya N; Cullere, Xavier; Lowell, Clifford A (2014) The multifaceted functions of neutrophils. Annu Rev Pathol 9:181-218|
|Venkatesh, Deepak; Ernandez, Thomas; Rosetti, Florencia et al. (2013) Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-? autocrine signaling to promote monocyte recruitment. Immunity 38:1025-37|
|Rosetti, Florencia; Tsuboi, Naotake; Chen, Kan et al. (2012) Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency. J Immunol 189:3714-23|
|Chen, Kan; Nishi, Hiroshi; Travers, Richard et al. (2012) Endocytosis of soluble immune complexes leads to their clearance by FcýýRIIIB but induces neutrophil extracellular traps via FcýýRIIA in vivo. Blood 120:4421-31|
|Niewczas, Monika A; Gohda, Tomohito; Skupien, Jan et al. (2012) Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol 23:507-15|
|Crispín, José C; Apostolidis, Sokratis A; Rosetti, Florencia et al. (2012) Cutting edge: protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism. J Immunol 188:3567-71|
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