title: S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis.
abstract: BACKGROUND
  A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined.
  
  
  OBJECTIVE
  The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB.
  
  
  METHODS
  The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques.
  
  
  RESULTS
  We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB.
  
  
  CONCLUSIONS
  Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.
authors.affiliation: 1 Division of Infectious Diseases, Department of Pediatrics, and.
authors.forename: Radha
authors.initials: R
authors.lastname: Gopal
authors.forename: Leticia
authors.initials: L
authors.lastname: Monin
authors.forename: Diana
authors.initials: D
authors.lastname: Torres
authors.forename: Samantha
authors.initials: S
authors.lastname: Slight
authors.forename: Smriti
authors.initials: S
authors.lastname: Mehra
authors.forename: Kyle C
authors.initials: KC
authors.lastname: McKenna
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fallert Junecko
authors.forename: Todd A
authors.initials: TA
authors.lastname: Reinhart
authors.forename: Jay
authors.initials: J
authors.lastname: Kolls
authors.forename: Renata
authors.initials: R
authors.lastname: Báez-Saldaña
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cruz-Lagunas
authors.forename: Tatiana S
authors.initials: TS
authors.lastname: Rodríguez-Reyna
authors.forename: Nathella Pavan
authors.initials: NP
authors.lastname: Kumar
authors.forename: Phillipe
authors.initials: P
authors.lastname: Tessier
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.forename: Enrique
authors.initials: E
authors.lastname: Becerril-Villanueva
authors.forename: Javier
authors.initials: J
authors.lastname: Baquera-Heredia
authors.forename: Bridgette
authors.initials: B
authors.lastname: Cumming
authors.forename: Victoria O
authors.initials: VO
authors.lastname: Kasprowicz
authors.forename: Adrie J C
authors.initials: AJ
authors.lastname: Steyn
authors.forename: Subash
authors.initials: S
authors.lastname: Babu
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaushal
authors.forename: Joaquín
authors.initials: J
authors.lastname: Zúñiga
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel-Moreno
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
mesh_terms: D000818:Animals; D040501:Calgranulin A / Q000276:immunology*; D040502:Calgranulin B / Q000276:immunology*; D018925:Chemokines / Q000276:immunology; D002630:Chemotactic Factors / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D015769:Granuloma, Respiratory Tract / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology*; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D018925:Chemokines; D002630:Chemotactic Factors; D016207:Cytokines; D018836:Inflammation Mediators
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