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Young disease transitioning B Sle
Young disease-transitioning B6·Sle1 mice show partial loss of leukocyte Axl versus B6 controls (data not shown). Further, BMDM from diseased B6·Sle1.Yaa mice do not express detectable levels of ADAM10 and TACE (ADAM17) but do express basal levels of Axl similar to wild type B6-derived BMDM (Supplemental Fig. 2A, B). Thus, leukocyte Axl shearing in SLE appears to occur mainly in the periphery in response to an inflammatory milieu. This is consistent with known upregulation of macrophage proteases in inflammatory conditions [38], [39], [40]. We speculate that Axl loss in macrophages may contribute to “flares”—periodic, severe worsening of SLE symptoms with no clear cause—by failing to appropriately rein in inflammatory cytokine secretion. This is supported by multiple reports and our observations correlating serum sAxl levels with disease severity on the SLEDAI (systemic lupus erythematosus disease activity index) scale [19], [20]. The loss of Axl from blood monocytes could decrease Axl anti-inflammatory signaling in two ways. First, cleavage of cell-surface Axl abrogates Axl signaling through the remaining “stump” receptor. This “cis” suppression of Axl anti-inflammatory signaling on macrophages is supported by our studies outlined here. Second, this cleavage produces a decoy receptor “sink” that may block Gas6 signaling in other cells. This “trans” suppression would affect cells in which Axl and/or other Gas6 receptors like Mer and Tyro3 remain intact. Because Gas6 has higher binding affinity to Axl than to other receptors [5], this sink may effectively abrogate TAM receptor signaling pathways in other cells. Additional study will be required to determine whether “trans” sAxl effects are physiologically significant (see Ref [31], Fig. 3 for preliminary data). The consequences of Axl shedding from annexin v are less clear. While we show that normal, healthy CD19+ mouse leukocytes express Axl, they upregulate Twist marginally upon Gas6 stimulation (see Ref [31], Fig. 2). It remains to be explored how Gas6-mediated Axl signaling affects B cells normally and in SLE. Type I interferons (IFN I) are known to be elevated in SLE but do not exert anti-inflammatory effects [47], [48], [49], [50]. Many studies have provided explanations for this phenomenon, including activation of different subsets of autoreactive cells [51]. The present study may offer an additional explanation of this phenomenon, as at least part of the IFN I mediated anti-inflammatory effect may be Axl-dependent [18]. Further study is warranted to address this possibility. Recent interest in sAxl in SLE serum has led to conflicting reports of significant versus insignificant correlation of serum sAxl and disease severity [19], [20], [21]. This may be due to variation in patient populations studied. Our patient cohorts in Fig. 1 and others reporting significant correlation of sAxl and disease have generally focused on Hispanic and African American patients and controls, whereas those reporting insignificant correlation comprise mainly European American patients and controls. Different reports also cite significantly decreased or increased Gas6 in severe SLE [14], [19], [20], [21], although these variations may be due to differences in measuring free versus sAxl-bound Gas6. Most report an increase. While the Axl ligand Gas6 is elevated in the serum of mice and humans with SLE, its anti-inflammatory activity may be blunted in leukocytes by Axl shearing. Conversely, Gas6 in the kidney contributes to nephritis and inflammation through Axl-mediated mesangial cell proliferation [14], [15], [16], [17]. In short, Axl signaling has opposing effects in mesangial cells (pro-disease) versus peripheral leukocytes (anti-inflammatory). Thus an Axl kinase inhibitor may exacerbate SLE by inhibiting Twist-mediated anti-inflammatory signaling in macrophages while a Gas6 homolog may exacerbate SLE by enhancing mesangial cell proliferation. Matrix metalloprotease inhibition, which would directly increase leukocyte but not mesangial cell Axl signaling, may be a more effective therapeutic intervention.