Human Lung-Resident Macrophages Express and Are Targets of Thymic Stromal Lymphopoietin in the Tumor Microenvironment.

Mariantonia Braile,Rosa Maria Di Crescenzo,Daniela Sorriento,Alfonso Fiorelli,Maria Rosaria Galdiero,Gilda Varricchi,Stefania Loffredo,Gianni Marone,Mario Santini

doi:10.3390/cells10082012

Abstract

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine highly expressed by epithelial cells and several innate and adaptive immune cells. TSLP exerts its biological effects by binding to a heterodimeric complex composed of TSLP receptor (TSLPR) and IL-7Rα. In humans, there are two TSLP isoforms: the short form (sfTSLP), constitutively expressed, and the long form (lfTSLP), which is upregulated in inflammation. TSLP has been implicated in the induction and progression of several experimental and human cancers. Primary human lung macrophages (HLMs), monocyte-derived macrophages (MDMs), and peripheral blood monocytes consitutively expressed sfTSLP mRNA. Incubation of HLMs, MDMs, and monocytes with lipopolysaccharide (LPS) or IL-4, but not with IL-13, induced TSLP release from HLMs. LPS, but not IL-4 or IL-13, induced CXCL8 release from HLMs. LPS, IL-4 alone or in combination with IL-13, induced the expression of lfTSLP, but not of sfTSLP from HLMs. Preincubation of HLMs with IL-4, alone or in combination with IL-13, but not IL-13 alone, synergistically enhanced TSLP release from LPS-activated macrophages. By contrast, IL-4, alone or in combination with IL-13, inhibited LPS-induced CXCL8 release from HLMs. Immunoreactive TSLP was detected in lysates of HLMs, MDMs, and monocytes. Incubation of HLMs with TSLP induced the release of proinflammatory (TNF-α), angiogenic (VEGF-A, angiopoietin 2), and lymphangiogenic (VEGF-C) factors. TSLP, TSLPR, and IL-7Rα were expressed in intratumoral and peritumoral areas of human lung cancer. sfTSLP and lfTSLP mRNAs were differentially expressed in peritumoral and intratumoral lung cancer tissues. The TSLP system, expressed in HLMs, MDMs, and monocytes, could play a role in chronic inflammatory disorders including lung cancer.

Highlights

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine [1,2] highly expressed by lung [3,4,5,6,7,8] and intestinal epithelial cells [9,10,11,12,13,14]
In a series of six different experiments, we investigated whether highly purified primary human lung macrophages (HLMs) constitutively express the TSLP receptor (TSLPR and interleukin 7 receptor-α (IL-7Rα)), the short-form TSLP and the long-form TSLP by different techniques
We examined the constitutive expression of thymic stromal lymphopoietin receptor (TSLPR) and IL-7Rα by two different techniques

Summary

Introduction

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine [1,2] highly expressed by lung [3,4,5,6,7,8] and intestinal epithelial cells [9,10,11,12,13,14]. Two isoforms (short and long) for TSLP have been identified in different human tissues [9,13]. The short-form TSLP (sfTSLP) is constitutively expressed in normal tissues, including bronchial and intestinal epithelial cells, keratinocytes, and lung fibroblasts [9,13,24,25,26], whereas the long-form TSLP (lfTSLP) is upregulated in inflammatory conditions [9,13]. There is evidence that TSLP can be cleaved by endogenous proteases in inflammatory conditions [8,14,27]

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Discussion

Conclusion