Distinct Roles of CSF-1 Isoforms in Lupus Nephritis

Abstract

Colony-stimulating factor-1 (CSF-1), the principal growth factor for macrophages, is increased in the kidney, serum, and urine of patients with lupus nephritis, and eliminating CSF-1 suppresses lupus in MRL-Fas lpr mice. CSF-1 has three biologically active isoforms: a membrane-spanning cell surface glycoprotein (csCSF-1), a secreted proteoglycan (spCSF-1), and a secreted glycoprotein (sgCSF-1); the role of each isoform in the circulation and kidney in autoimmune disease is not well understood. Here, we constructed mutant MRL-Fas lpr mice that only express csCSF-1 or precursors of the spCSF-1 and sgCSF-1 isoforms. Both csCSF-1 and spCSF-1 shifted monocytes toward proinflammatory, activated populations, enhancing their recruitment into the kidney during lupus nephritis. With advancing lupus nephritis, spCSF-1 was the predominant isoform responsible for increasing circulating CSF-1 and, along with the csCSF-1 isoform, for increasing intrarenal CSF-1. Thus, csCSF-1 appears to initiate and promote the local activation of macrophages within the kidney. Intrarenal expression of csCSF-1 and spCSF-1 increases with advancing nephritis, thereby promoting the intrarenal recruitment of monocytes and expansion of Ly6C hi macrophages, which induce apoptosis of the renal parenchyma. Taken together, these data suggest that the three CSF-1 isoforms have distinct biologic properties, suggesting that blocking both circulating and intrarenal CSF-1 may be necessary for therapeutic efficacy.

IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease

“…While ischemia-induced IL-34 drives AKI and thereby worsens subsequent CKD, our prior studies (4) and others (24,25) indicate that CSF-1 hastens AKI repair after I/R. However, CSF-1 mediates repair in AKI and conversely escalates spontaneous (MRL-Fas lpr lupus nephritis) (3,5,7,8,20) and induced (unilateral ureteral obstruction) (22,23) CKD. This divergent role of CSF-1 is analogous to epidermal growth-factor receptor signaling in AKI and CKD.…”

“…As Mø mediate kidney repair and destruction, we reasoned that the principal molecule required for Mø survival, proliferation, and activation -CSF-1 -is central to regulating the fate of the kidney. Our prior studies show that CSF-1 expression is beneficial in kidneys destined to repair (4) and, conversely, harmful in kidneys destined for autoimmunemediated chronic disease (3,(5)(6)(7)(8).…”

“…Moreover, while both IL-34 and CSF-1 signal through c-FMS, IL-34 has a second recently uncovered receptor, PTP-ζ, at least in the brain (19). Although CSF-1-mediated mechanisms during renal inflammation are well documented by our laboratory and others (3,5,7,8,(20)(21)(22)(23)(24)(25), the role of IL-34 in inflammation, particularly in the kidney, has not been explored. The central issues are: (i) do IL-34-dependent, Mø-mediated mechanisms augment or thwart AKI and subsequent CKD; (ii) are CSF-1 and IL-34 redundant during renal injury; (iii) do IL-34-dependent, Mø-mediated mechanisms within and/ or outside the kidney alter renal injury; (iv) are IL-34-dependent mechanisms responsible for shifting the dominant intrarenal Mø phenotype prior to and/or after I/R; and (v) is intrarenal and systemic IL-34 expression relevant to ischemia-incited human AKI and subsequent CKD?…”

Monoclonal antibody against macrophage colony-stimulating factor suppresses circulating monocytes and tissue macrophage function but does not alter cell infiltration/activation in cutaneous lesions or clinical outcomes in patients with cutaneous lupus erythematosus

“…These human data show incomplete suppression of circulating monocytes under the conditions in this study, which may have contributed to the lack of efficacy observed in lesional sites. Regarding suppression of local M-CSF activity, there are three homodimeric isoforms of the M-CSF ligand, which have specific spatial and temporal expression resulting in unique functional activities [38]. Although the epitope for PD-0360324 is contained within the N-terminal 146 amino acid region of M-CSF, which is conserved in all isoforms (data not shown), we cannot rule out the potential for differences in tissue penetration or pharmacokinetic requirements for suppression of each isoform in vivo.…”

Imatinib

“…3,34 Macrophages propagate kidney injury through secretion of inflammatory cytokines, production of profibrotic growth factors, and generation of reactive oxygen species. [35][36][37] Macrophage depletion attenuated fibrosis in a unilateral ureteral obstruction (UUO) model of injury, suggesting that macrophage infiltration may be deleterious.…”