Sunlight Triggers Cutaneous Lupus through a CSF-1-Dependent Mechanism in MRL-Fas lpr Mice

Abstract

Sunlight (UVB) triggers cutaneous lupus erythematosus (CLE) and systemic lupus through an unknown mechanism. We tested the hypothesis that UVB triggers CLE through a CSF-1-dependent, macrophage (Mø)-mediated mechanism in MRL-Faslpr mice. By constructing mutant MRL-Faslpr strains expressing varying levels of CSF-1 (high, intermediate, none), and use of an ex vivo gene transfer to deliver CSF-1 intradermally, we determined that CSF-1 induces CLE in lupus-susceptible MRL-Faslpr mice, but not in lupus-resistant BALB/c mice. UVB incites an increase in Møs, apoptosis in the skin, and CLE in MRL-Faslpr, but not in CSF-1-deficient MRL-Faslpr mice. Furthermore, UVB did not induce CLE in BALB/c mice. Probing further, UVB stimulates CSF-1 expression by keratinocytes leading to recruitment and activation of Møs that, in turn, release mediators, which induce apoptosis in keratinocytes. Thus, sunlight triggers a CSF-1-dependent, Mø-mediated destructive inflammation in the skin leading to CLE in lupus-susceptible MRL-Faslpr but not lupus-resistant BALB/c mice. Taken together, CSF-1 is envisioned as the match and lupus susceptibility as the tinder leading to CLE.

Circulating CSF-1 Promotes Monocyte and Macrophage Phenotypes that Enhance Lupus Nephritis

“…25,26 On the other hand, CSF-1 is increased in the circulation in neonates, well in advance of renal injury in MRL-Fas lpr mice. 19 Thus, it is possible that a circulating CSF-1-dependent mechanism leads to amplifying intrarenal CSF-1.…”

“…17,29,30 Using the CSF-1 transgenic MRL-Fas lpr line that promotes lupus nephritis we have used in the study presented here, we previously detected a more rapid onset of cutaneous disease (discoid lupus) compared with WT mice. 25 Moreover, sunlight exposure induces CSF-1 in keratinocytes in the epidermis that spills over into the circulation and, in turn, leads to the recruitment and activation of Mø (F4/80 ϩ CD68 ϩ ) in the skin. Thus, CSF-1 sets in motion Mø-mediated events leading to the destruction of keratinocytes and discoid lupus.…”

“…Thus, CSF-1 sets in motion Mø-mediated events leading to the destruction of keratinocytes and discoid lupus. 25 Because disease in MRL-Fas lpr is a multiorgan disease involving kidney, skin, and other tissues, 31 many tissues may contribute and respond to increasing circulating CSF-1 levels. Because our study indicates that circulating CSF-1 is instrumental in mediating renal injury, we speculate that CSF-1 generated within the kidney that is released into the circulation has an effect on cutaneous disease and other tissues, and vice versa.…”

“…25 Undiluted serum and urine samples were analyzed directly. The tissues used for homogenates were from mice perfused with PBS through the heart to flush out CSF-1 in the circulation.…”

“…Figure 7), it is likely that most EGFP ϩ BM in the kidney reflects recruitment rather than proliferation. 6 CSF-1 directly activates Mø (CD68 ϩ ), 25 and these Mø, in turn, release mediators that induce TEC apoptosis in vitro. 26 sion in MRL-Fas lpr mice increases the number of Mo seeded from the BM into the circulation; shifts these Mo toward an inflammatory and activated phenotype; and, in turn, hastens the rise of activated Mø in the kidney that induces TEC apoptosis.…”