The prominent expression of Mer in the kidney has raised the question of its role in this organ, especially in light of the susceptibility of the kidney to antibody-mediated injury. The present study demonstrates, for the first time, that Mer expression is on mesangial and endothelial cells within the glomerulus. The partial overlap of nephrin with Mer expression could be argued by the interdigitating processes between podocytes (epithelium) and capillaries (endothelium), the latter has the maximum expression of Mer. Mer-KO mice kidneys are far more susceptible to antibody-mediated damage in the absence of a functional Mer molecule. These findings extend previous work ascribing a protective role to Mer in other kinds of inflammation [8
], and contrast with the previously reported role of Axl in accelerating renal disease [13
]. Thus, Mer and Axl, two receptor kinases and members of the same subfamily, seem to serve opposing roles in modulating or promoting glomerular inflammation. The contrasting roles of Mer and Axl in vivo may be dependent on their relative expression (much greater for Mer in the basal state) and in the availability of ligands. Protein S, a negative regulator of coagulation, is abundant in unstimulated plasma and may serve to bind to the large amounts of Mer in healthy kidney [10
]. When kidneys become inflamed, both Gas6 and Axl expression is increased, opening up the possibility that involvement of the Axl pathway may serve to exacerbate inflammation once it begins. Further experiments will be required to clarify the apparently complex relationship between Axl and Mer in renal pathology.
A key function of Mer is to help in clearing apoptotic cells [17
]. Our data confirm that Mer serves this function in the kidney, where many cells undergo apoptosis, especially during nephritis. It is possible that Mer’s protective role is partially through the clearance of apoptotic cells, so that they cannot serve to stimulate further autoimmunity through progression to necrosis and provision of autoimmunogenic nuclear antigens. Through this mechanism, almost any renal insult causing apoptosis might have the potential to stimulate autoimmunity if nuclear debris is allowed to accumulate. Mer may serve to protect against secondary formation of anti-nuclear antibodies when kidneys undergo injury of any kind.
Increased infiltration with leukocytes is now recognized in virtually all forms of glomerular injury. The adherence and subsequent transmigration of circulating monocytes into glomerular mesangium occurs early in the development of renal diseases. Our studies reinforce previous observations that myeloid cell infiltration in the glomeruli and the tubulointerstitium is essential to disease in the NTS-nephritis model [1
]. In previous studies [16
] and in present experiments (), elevated amount of TNF-α was observed in inflamed organ lacking Mer. TNF-α has been approved by many in vitro and in vivo studies, as a fundamental proinflammatory cytokine involved in the pathogenesis of glomerular injury [1
]. Mesangial cells activated by TNF-α transcribe MCP-1 mRNA in a dose- and time-dependent manner [29
]. MCP-1 has been thought to play an important role in the recruitment and accumulation of monocytes within the glomerulus. Accumulated observations suggest that MCP-1 accounts for nearly all of the monocyte chemotactic activity [30
]. Matsukawa A., et al demonstrated that MCP-1 serves as an indirect mediator to attract neutrophils via the production of leukotriene B4
]. The striking effect of Mer in preventing neutrophil infiltration appears to be due to a dampening of MCP-1 expression, and adds this cytokine to the list of cytokines whose production can be regulated by Mer ligation. Together with previous data [1
], IL-1 and IL-6 production also appeared to be down regulated by Mer, contributing to its protective role.
The increased expression of Mer in injured kidneys in these experiments deserves comment. Mer expression has also been observed to increase on B cells in chronic GVH disease. In the present model, increased Mer expression may serve as an additional regulatory mechanism to protect renal tissue against self-reactive humoral immunity, and therapeutics aimed at enhancing Mer expression might be rational agents to reduce ongoing renal inflammation.
The present studies reinforce the view that Mer and its ligands are key participants in autoimmune and inflammatory processes. Better understanding of how capillary rich organs such as the kidney are protected through Mer may lead to new approaches to modulate immune-mediated injury.