Autocrine IL-10 activation of the STAT3 pathway is required for pathological macrophage differentiation in polycystic kidney disease

Abstract

Polycystic kidney disease (PKD) is characterized by slow expansion of fluid-filled cysts derived from tubules within the kidney. Cystic expansion results in injury to surrounding parenchyma and leads to inflammation, scarring and ultimately loss of renal function. Macrophages are a key element in this process, promoting cyst epithelial cell proliferation, cyst expansion and disease progression. Previously, we have shown that the microenvironment established by cystic epithelial cells can ‘program’ macrophages, inducing M2-like macrophage polarization that is characterized by expression of markers that include Arg1 and Il10. Here, we functionally characterize these macrophages, demonstrating that their differentiation enhances their ability to promote cyst cell proliferation. This observation indicates a model of reciprocal pathological interactions between cysts and the innate immune system: cyst epithelial cells promote macrophage polarization to a phenotype that, in turn, is especially efficient in promoting cyst cell proliferation and cyst growth. To better understand the genesis of this macrophage phenotype, we examined the role of IL-10, a regulatory cytokine shown to be important for macrophage-stimulated tissue repair in other settings. Herein, we show that the acquisition of the pathological macrophage phenotype requires IL-10 secretion by the macrophages. Further, we demonstrate a requirement for IL-10-dependent autocrine activation of the STAT3 pathway. These data suggest that the IL-10 pathway in macrophages plays an essential role in the pathological relationship between cysts and the innate immune system in PKD, and thus could be a potential therapeutic target.

Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer

“…The signals from lactate that elicit M2-like functional polarization of TAMs are still not fully understood. Many signals are involved in M2-like macrophage polarization, for instance, ERK1/2, STAT3, HIF1a, and STAT6 and so forth, the activation of which can upregulate M2 macrophage polarization via different ways in the TME [5,15]. In this study, we found that lactate activated ERK1/2 and STAT3 signaling in macrophages.…”

“…Macrophages in the tumor microenvironment can be educated by cancer cells [15]. To examine whether cancer cell-derived lactate can modulate macrophage M2 activation, Western blot and QPCR analyses of bone marrow-derived macrophages (BMDMs) and the THP-1 cell line showed that lactate enhanced the expression of M2 macrophage markers.…”

Interactions between Macrophages and Cyst-Lining Epithelial Cells Promote Kidney Cyst Growth in Pkd1-Deficient Mice

“…3 Although the proproliferative function of macrophages in connection with cyst-lining epithelial cells (CLECs) has been explored in a few studies, the specific mechanism remains unclear. [4][5][6] Macrophages are not homogenous, and they are generally categorized into two distinct phenotypes: classically activated (M1) or alternatively activated (M2). 7 ARG1 is a classic M2-like molecular marker for macrophages and abundant M2-type macrophages are detected in polycystic kidney tissue.…”

JAK2 is highly expressed by cyst-lining cells and regulates cystogenesis

“…In this paper we find that curcumin targets JAK2 by causing it to become inactive leading to reduced STAT3 activity. Given that STAT3 may be cystogenic, (8,25,30,31), it stands to speculate that some of the protection offered by curcumin may be via inhibition of STAT3 activity. However, high doses of curcumin are needed to inhibit STAT3, as shown in our study (25-100μM) and gaining these concentrations in plasma is difficult, given curcumin’s reduced bioavailability (24).…”