title: Mycobacterium tuberculosis-induced apoptotic neutrophils trigger a pro-inflammatory response in macrophages through release of heat shock protein 72, acting in synergy with the bacteria.
abstract: Mycobacterium tuberculosis (Mtb) survive inside macrophages by manipulating microbicidal functions such as phago-lysosome fusion, production of reactive oxygen species and nitric oxide, and by rendering macrophages non-responsive to IFN-gamma. Mtb-infected lung tissue does however not only contain macrophages, but also significant numbers of infiltrating polymorphonuclear neutrophils (PMN). These are able to phagocytose and kill ingested Mtb, but are short-lived cells that constantly need to be removed from tissues to avoid tissue damage. Phagocytosis of aged or UV-induced apoptotic PMN by macrophages induce an anti-inflammatory response in macrophages. However, in the present study, we show that engulfment of Mtb-induced apoptotic PMN by macrophages initiates secretion of TNF-alpha from the macrophages, reflecting a pro-inflammatory response. Moreover, Mtb-induced apoptotic PMN up-regulate heat shock proteins 60 and 72 (Hsp60, Hsp72) intracellularly and also release Hsp72 extracellularly. We found that both recombinant Hsp72 and released Hsp72 enhanced the pro-inflammatory response to both Mtb-induced apoptotic PMN and Mtb. This stimulatory effect of the supernatant was abrogated by depleting the Hsp72 with immunoprecipitation. These findings indicate that released Hsp72 from Mtb-infected PMN can trigger macrophage activation during the early stage of Mtb infections, thereby creating a link between innate and adaptive immunity.
authors.affiliation: Division of Medical Microbiology, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. alexander.persson@imk.liu.se
authors.forename: Y Alexander Z
authors.initials: YA
authors.lastname: Persson
authors.forename: Robert
authors.initials: R
authors.lastname: Blomgran-Julinder
authors.forename: Sayma
authors.initials: S
authors.lastname: Rahman
authors.forename: Limin
authors.initials: L
authors.lastname: Zheng
authors.forename: Olle
authors.initials: O
authors.lastname: Stendahl
mesh_terms: D017209:Apoptosis; D002478:Cells, Cultured; D050884:HSP72 Heat-Shock Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009504:Neutrophils / Q000502:physiology*; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D050884:HSP72 Heat-Shock Proteins