SPARC coordinates extracellular matrix remodeling and efficient recruitment to and migration of antigen-specific T cells in the brain following infection

Kathryn E Mcgovern,Shahani Noor,Clément N David,Danielle Worth,Andre Obenaus,J Philip Nance,Monica J Carson,Tyler A Landrith,Dimitrios Morikis,Emma H Wilson,Reed E S Harrison

doi:10.1038/s41598-021-83952-0

Abstract

Central nervous system (CNS) injury and infection can result in profound tissue remodeling in the brain, the mechanism and purpose of which is poorly understood. Infection with the protozoan parasite Toxoplasma gondii causes chronic infection and inflammation in the brain parenchyma. Control of parasite replication requires the continuous presence of IFNγ-producing T cells to keep T. gondii in its slowly replicating cyst form. During infection, a network of extracellular matrix fibers, revealed using multiphoton microscopy, forms in the brain. The origin and composition of these structures are unknown but the fibers have been observed to act as a substrate for migrating T cells. In this study, we show a critical regulator of extracellular matrix (ECM) remodeling, Secreted Protein, Acidic, Rich in Cysteine (SPARC), is upregulated in the brain during the early phases of infection in the frontal cortex. In the absence of SPARC, a reduced and disordered fibrous network, increased parasite burden, and reduced antigen-specific T cell entry into the brain points to a role for SPARC in T cell recruitment to and migration within the brain. We also report SPARC can directly bind to CCR7 ligands CCL19 and CCL21 but not CXCL10, and enhance migration toward a chemokine gradient. Measurement of T cell behavior points to tissue remodeling being important for access of immune cells to the brain and facilitating cellular locomotion. Together, these data identify SPARC as an important regulatory component of immune cell trafficking and access to the inflamed CNS.

Highlights

Central nervous system (CNS) injury and infection can result in profound tissue remodeling in the brain, the mechanism and purpose of which is poorly understood
During chronic T. gondii infection, a network of fibers is established within the CNS to which migrating immune cells associate[37]
We focused our imaging in the frontal cortex since the second harmonic generation (SHG) signal is in greatest abundance where T. gondii is most c ommon[30] (Fig. 1a)

Summary

Introduction

Central nervous system (CNS) injury and infection can result in profound tissue remodeling in the brain, the mechanism and purpose of which is poorly understood. A functional immune response critically depends on the ability of effector cells to migrate to sites of infection. SHG can be used to visualize non-centrosymmetric structures, the most common of which are collagen fibers[5] Studies using this technique highlight the importance of tissue matrix for the migration of immune cells within the lymph node, skin and tumors[6,7,8,9,10,11]. The ability of IFNγproducing T cells to migrate to sites of infection in the brain is paramount in controlling the replication of the parasite Work by this lab and others have shown chemokines like CCL21, CCL19, and CXCL10 are upregulated in the brain[34,35,36,37]. The composition and source of this major tissue remodeling event is unknown, we hypothesized that this network is a mechanism for effector cells to migrate to sites of infection within the brain

Methods

Results

Conclusion