Altered Circulating Levels of Matrix Metalloproteinases and Inhibitors Associated with Elevated Type 2 Cytokines in Lymphatic Filarial Disease

Rajamanickam Anuradha,Nathella Pavankumar,Thomas B Nutman,Thomas B Nutman,Subash Babu,Subash Babu,Jovvian P George,Vasanthapuram Kumaraswami,Patrick J Lammie

doi:10.1371/journal.pntd.0001681

Abstract

BackgroundInfection with Wuchereria bancrofti can cause severe disease characterized by subcutaneous fibrosis and extracellular matrix remodeling. Matrix metalloproteinases (MMPs) are a family of enzymes governing extracellular remodeling by regulating cellular homeostasis, inflammation, and tissue reorganization, while tissue-inhibitors of metalloproteinases (TIMPs) are endogenous regulators of MMPs. Homeostatic as well as inflammation-induced balance between MMPs and TIMPs is considered critical in mediating tissue pathology.MethodsTo elucidate the role of MMPs and TIMPs in filarial pathology, we compared the plasma levels of a panel of MMPs, TIMPs, other pro-fibrotic factors, and cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag−) active infection to those with clinically asymptomatic infections (INF) and in those without infection (endemic normal [EN]). Markers of pathogenesis were delineated based on comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag− compared to EN).Results and ConclusionOur data reveal that an increase in circulating levels of MMPs and TIMPs is characteristic of the filarial disease process per se and not of active infection; however, filarial disease with active infection is specifically associated with increased ratios of MMP1/TIMP4 and MMP8/TIMP4 as well as with pro-fibrotic cytokines (IL-5, IL-13 and TGF-β). Our data therefore suggest that while filarial lymphatic disease is characterized by a non-specific increase in plasma MMPs and TIMPs, the balance between MMPs and TIMPs is an important factor in regulating tissue pathology during active infection.

Highlights

Lymphatic filariasis (LF) is characterized by dysfunction of lymphatics that can lead to severe and often irreversible lymphedema and elephantiasis [1,2]
While the infection is mostly clinically asymptomatic, approximately 40 million people suffer from overt, morbid clinical pathology characterized by swelling of the scrotal area and lower limbs
Matrix metalloproteinases are a family of circulating and tissue proteins that influence the development of tissue fibrosis

Summary

Introduction

Lymphatic filariasis (LF) is characterized by dysfunction of lymphatics that can lead to severe and often irreversible lymphedema and elephantiasis [1,2]. It is assumed that both parasite products and the host inflammatory response lead to lymphatic dysfunction and lymphangiogenesis that, in turn, predisposes infected individuals to secondary bacterial and fungal infection [2,4,5]. Host-parasite interactions as well as secondary infections trigger inflammatory reactions in the skin and subcutaneous tissue with underlying fibrosis and cellular hyperplasia processes resulting in lymphedema and elephantiasis [2,4]. Lymphatic dysfunction and localized/systemic immunologic and inflammatory responses are important features of lymphatic pathology [6], perturbations in extracellular matrix (ECM) architecture and subsequent remodeling are associated with filarial disease [7,8,9]. Infection with Wuchereria bancrofti can cause severe disease characterized by subcutaneous fibrosis and extracellular matrix remodeling. Homeostatic as well as inflammation-induced balance between MMPs and TIMPs is considered critical in mediating tissue pathology

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Results

Discussion

Conclusion