Lupus and innate immunity: The macrophage as a potential therapeutic target
Chalmers, Samantha A.
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Systemic lupus erythematosus (SLE) is an autoimmune disease which manifests in multiple end organs including kidney (lupus nephritis, LN), skin (cutaneous lupus erythematosus, CLE), and brain (neuropsychiatric SLE, NPSLE). Current treatment options for SLE and its various end organ pathologies are less than ideal, and tend to rely upon broad immune suppression, despite the risk for potentially serious side effects and no guarantee of remission.;Macrophages are cells of the innate immune system which play critical roles in both host immunity, as well as tissue homeostasis. Macrophages are present in nearly every tissue, and possess a high degree of plasticity which allows them to assume a myriad of functional phenotypes depending on the context of the tissue environment they are exposed to. Despite the vital role that macrophages play in maintaining healthy tissues, when macrophage function goes awry it can lead to potentially serious disease. SLE has long been considered a disease of the adaptive immune system; however, our hypothesis was that macrophages are an important contributor to SLE pathogenesis in various end organ manifestations, and that various methods of targeting this cell type may have therapeutic potential in SLE.;We first explored the role of macrophages in the pathogenesis of LN using a well-established, inducible model of this disease known as nephrotoxic serum nephritis (NTN). This disease model depends on the passive transfer of nephrotoxic antibodies to induce kidney disease which accurately mimics many aspects of human disease. Initially, we targeted macrophages in NTN using a drug known as GW2580, a kinase inhibitor monospecific for the colony stimulating factor 1 receptor (CSF-1R). Targeting of this receptor depletes both tissue resident macrophages and inhibits the recruitment of inflammatory monocytes. We found that when mice were given this drug preventatively, they were protected from the high levels of proteinuria, serum BUN, and serum creatinine seen in control sick mice. Furthermore, treated mice had significantly improved renal pathology, normalized expression of inflammatory cytokines in the kidney, and decreased renal T cell infiltration. Flow cytometry and immunofluorescent staining confirmed the depletion of macrophages in the GW2580 treated mice. Additionally, delayed treatment of GW2580 until after the initiation of disease also provided significant renal protection to the mice. A more recent study using a genetic approach revealed that mice deficient of NF-x13 in their myeloid cells have ameliorated nephritis when subjected to NTN as compared to WT mice, further implicating the pro-inflammatory activity of macrophages in the disease pathogenesis of LN. We next assessed the effect of macrophage depletion in a systemic and spontaneous model of SLE using the MRL/lpr mouse model. In two separate experiments, mice were treated with two different CSF-1R kinase inhibitors: GW2580 and PLX3397. In both cases, treated mice had amelioration of renal disease, and interestingly, of neuropsychiatric and cutaneous disease as well.;We also targeted macrophages via inhibition of Bruton's tyrosine kinase (BTK), which is important to B cell function, but also critical for macrophage activation and polarization. In both the NTN inducible model of LN, and in the spontaneous MRL/lpr mouse model, BTK inhibition prevented the development of kidney disease and significantly extended the survival of treated mice. Interestingly, in the NTN model of disease, we found that treatment with the BTK inhibitor was able to reverse established, severe nephritis. Moreover, in the MRL/lpr mouse, BTK inhibition was also able to ameliorate skin and brain involvement.;Taken together, these data strongly implicate macrophages as important mediators of SLE pathogenesis, in multiple end organ manifestations of disease; consequently, macrophages represent a promising target for the development of future SLE treatments.
- Theses and Dissertations