Innate Anti-microbial and Anti-chemotaxis Properties of Progranulin in an Acute Otitis Media Mouse Model

Abstract

Acute otitis media (AOM) is one of the most common infectious diseases primarily caused by Streptococcus pneumoniae (S.pn) among children. Progranulin (PGRN) is a multifunctional growth factor widely expressed in various tissues and cells. Studies have confirmed that PGRN is involved in the development of a variety of inflammatory diseases. We found that the expression of PGRN increased significantly in the middle ear of wild mice with AOM. However, its physiological functions in AOM still remain unknown. To examine the role of PGRN during AOM, we established an acute otitis media model in both C57BL/6 wild mice and PGRN-deficient (PGRN−/−) mice via transbullar injection with S.pn clinical strain serotype 19F. Interestingly, we observed dual results: on one hand, macrophage recruitment notably increased in PGRN−/− mice compared with WT mice; on the other hand, the overall bacterial clearance was surprisingly dampened in PGRN−/− mice. The enhanced recruitment of macrophages was associated with increased production of chemokine (C-C motif) ligand 2 (CCL2), while the decreased bacterial clearance was associated with impaired endocytosis capacity of macrophages. The scavenging ability of bacteria in PGRN−/− mice was recovered with administration of recombinant PGRN. These results suggested a novel dual role of PGRN in affecting the activities of macrophages.

Generation of cryopreserved macrophages from normal and genetically engineered human pluripotent stem cells for disease modelling

“…Additionally, Wang et al . [ 41 ] reported an enhanced recruitment of live macrophages with the decreased bacterial clearance, impaired endocytosis capacity of macrophages accompanied with Progranulin (PGRN) deficiency and finally, Cronk et al . [ 42 ] reported on the differential gene expression profile on live Mecp2-null peritoneal macrophages implying a key role of this gene in sustaining macrophage function [ 42 ].…”

“…Side by side comparison of all live end stage macrophages cultures derived from SNCA A53T iPSC, GRN R493X iPSC, and MECP2 HM iPSC revealed a strong impairment of phagocytic function when compared to live end stage parental iPSC derived macrophages (S4 Fig) . This observation supports data published by Haenseler et al [14] on the impairment in phagocytic functions in live iPSC-derived macrophages from PD patients with SNCA Triplication and A53T mutations. Additionally, Wang et al [41] reported an enhanced recruitment of live macrophages with the decreased bacterial clearance, impaired endocytosis capacity of macrophages accompanied with Progranulin (PGRN) deficiency and finally, Cronk et al [42] reported on the differential gene expression profile on live Mecp2-null peritoneal macrophages implying a key role of this gene in sustaining macrophage function [42].…”

Progranulin Regulates Inflammation and Tumor

“…PGRN is a necessary secretory cofactor to enhance the driving response of TLR 9 to CpG-ODNs. As a key soluble cofactor in TLR 9 signal transduction, PGRN is related to innate immunity [ 85 - 89 ].…”

Current Understanding of Host Genetics of Otitis Media

“…Recently, Wang et al found a multifunctional growth factor, Progranulin (PGRN), was involved in AOM in an unusual way in the study of PGRN-deficient (PGRN -/-) mouse model (Wang et al, 2018). After Spn inoculation, PGRN -/mice exhibited increased macrophage recruitment in ME but delayed bacteria clearance.…”

“…After Spn inoculation, PGRN -/mice exhibited increased macrophage recruitment in ME but delayed bacteria clearance. They found the production of CCL2 is increased, which could contribute to enhanced macrophage recruitment, whereas the delayed bacteria clearance is most likely due to impaired endocytosis capacity of macrophages (Wang et al, 2018).…”