TY - JOUR
T1 - S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis
AU - Gopal, Radha
AU - Monin, Leticia
AU - Torres, Diana
AU - Slight, Samantha
AU - Mehra, Smriti
AU - McKenna, Kyle C.
AU - Junecko, Beth A.Fallert
AU - Reinhart, Todd A.
AU - Kolls, Jay
AU - Báez-Saldańa, Renata
AU - Cruz-Lagunas, Alfredo
AU - Rodríguez-Reyna, Tatiana S.
AU - Kumar, Nathella Pavan
AU - Tessier, Phillipe
AU - Roth, Johannes
AU - Selman, Moisés
AU - Becerril-Villanueva, Enrique
AU - Baquera-Heredia, Javier
AU - Cumming, Bridgette
AU - Kasprowicz, Victoria O.
AU - Steyn, Adrie J.C.
AU - Babu, Subash
AU - Kaushal, Deepak
AU - Zúñiga, Joaquín
AU - Vogl, Thomas
AU - Rangel-Moreno, Javier
AU - Khader, Shabaana A.
PY - 2013/11/1
Y1 - 2013/11/1
N2 - Rationale:Ahallmark 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. Objectives: 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. Measurements and Main Results: We demonstrate that in human patients with active TB and in nonhuman primatemodels of M. tuberculosis infection, neutrophils producing S100 proteins are dominantwithin the inflammatory lung granulomas seen during active TB. Using themouse model of TB, we demonstrate that the exacerbated lung inflammation seenasaresultofneutrophilicaccumulation isdependentonS100A8/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 keratinocytechemoattractant, canbeusedaspotential surrogatebiomarkers 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/A9proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.
AB - Rationale:Ahallmark 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. Objectives: 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. Measurements and Main Results: We demonstrate that in human patients with active TB and in nonhuman primatemodels of M. tuberculosis infection, neutrophils producing S100 proteins are dominantwithin the inflammatory lung granulomas seen during active TB. Using themouse model of TB, we demonstrate that the exacerbated lung inflammation seenasaresultofneutrophilicaccumulation isdependentonS100A8/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 keratinocytechemoattractant, canbeusedaspotential surrogatebiomarkers 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/A9proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.
KW - Granuloma
KW - Inflammation
KW - Neutrophil
KW - S100A8/A9 proteins
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=84887313029&partnerID=8YFLogxK
U2 - 10.1164/rccm.201304-0803OC
DO - 10.1164/rccm.201304-0803OC
M3 - Article
C2 - 24047412
AN - SCOPUS:84887313029
SN - 1073-449X
VL - 188
SP - 1137
EP - 1146
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 9
ER -